Glioblastoma is the most common and most aggressive of the primary malignant brain tumors in adults. Annually there are approximately 13,000 cases of GBM diagnosed, with historical 1 year and 5 year survival rates of 34.6% and 4.75% respectively. While concomitant chemoradiotherapy with temozolomide remains the standard of care for initial treatment, all patients eventually require salvage therapy and angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) pathway are standard in this setting. This application proposes a prospective, open-label, phase 2 study combining TH-302 at 670mg/m2 given every 2 weeks with bevacizumab in 33 patients with glioblastoma. Bevacizumab will be administered at 10mg/kg as established standard of care. TH-302 is a nitroimidazole prodrug of the cytotoxin, bromo-isophosphoramide mustard (Br-IPM). When exposed to hypoxic conditions, TH-302 is reduced at the nitroimadazole site of the prodrug by intracellular reductases leading to the release of Br-IPM. Br-IPM can then act as a DNA crosslinking agent. The investigators report that in vitro cytotoxicity and clonogenic assays indicate that TH-302 has little activity under normoxic conditions but is highly cytotoxic under hypoxic conditions. Patients will be followed by magnetic resonance imaging (MRI) until disease progression. The primary endpoint will be median progression free survival (PFS), with secondary end points of overall survival (OS) and safety. Significance in survival will be assessed by log-rank analysis with comparison to historical controls.
The specific aims of the study are to: 1) establish the efficacy of TH-302 in glioblastoma patients progressing on bevacizumab, 2) characterize hypoxic volume, cerebral blood flow, and oxygen extraction fraction (OEF) in patients undergoing treatment with TH-302, and 3) correlate changes in known molecular markers of bevacizumab de novo resistance, acquired resistance, and tumor hypoxia with tumor response, time to progression, and patient survival.
Glioblastoma is an incurable brain tumor which shows low levels of oxygen due to its rapid growth. A new type of chemotherapy is being studied in this proposal, which is only activated by low levels of oxygen seen in the tumor. We plan to assess the benefit of this drug in patients, together with imaging and blood studies that could potentially reveal which patients are the most likely to benefit.
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