DD-02PHARMACODYNAMIC BIOMARKER ASSESSMENTS IN A PHASE I/II TRIAL OF THE HYPOXIA-ACTIVATED PRODRUG TH-302 AND BEVACIZUMAB IN BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA

BACKGROUND: Glioblastoma (GBM) remains an incurable malignancy with rapid progression and poor survival. GBM exhibits a hypoxic nature, and treatment with bevacizumab (BEV) may increase intratumoral hypoxia. TH-302 is an investigational prodrug that selectively releases the DNA cross-linker (Br-IPM) under hypoxic conditions. A phase I/II trial (NCT01403610) is evaluating the safety and efficacy of combined TH-302 and BEV treatment in patients with BEV-refractory GBM and investigating pharmacodynamics biomarkers. METHODS: Patients were randomized to TH-302 single dose (575 mg/m2) or placebo, administered one day before surgery, followed by TH-302 (240-670 mg/m2) + BEV treatment until disease progression. Before surgery, pimonidazole (Pimo) was administered to label hypoxia and the excised tumor tissue was processed for immunohistochemistry. Endogenous plasma metabolites and plasma carbonic anhydrase IX (CA-IX) were also assessed. RESULTS: Immunohistochemistry was conducted on 11 resected tumors. A strong correlation and co-localization was observed between Pimo (exogenous hypoxia marker) and CA-IX (endogenous hypoxia marker) expression (r = 0.9, p < 0.001). Plasma CA-IX levels correlated well with tissue CA-IX expression. The hypoxic fraction tended to be higher in patients with a stable disease or partial tumor responses. Patients treated with TH-302 prior to surgery tended to have higher levels of γH2AX positive cells, indicating increased DNA damage, and lower Ki67 (a proliferation marker) compared with patients who received placebo. Patients treated with a single dose of TH-302 prior to surgery with higher levels of γH2AX-positive cells tended to have better outcome. Metabolomic profiles in plasma and in tumor tissue differed with degree of hypoxia. CONCLUSION: The results suggest that CA-IX as a hypoxia marker might be a predictive biomarker for TH-302 and γH2AX a response biomarker for TH-302. Correlative studies show metabolomic profile varies with tumor hypoxia degree, indicating plasma metabolites for further study as potential prognostic or treatment response markers.