AT-12 PHASE 1/2 STUDY OF TH-302, INVESTIGATIONAL HYPOXIA-ACTIVATED PRODRUG, AND BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 16; no. suppl 5; pp. v10 - v11
• Main Authors: Brenner, A., Floyd, J., Eng, C., Kroll, S., Fichtel, L., Gruslova, A., Lodi, A., Tiziani, S.
• Format: Journal Article
• Language: English
• Published: 01.11.2014
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou237.12

BACKGROUND: Hypoxia is implicated in the pathogenesis of glioblastoma multiforme (GBM), and greater hypoxic burden is associated with poorer outcomes in GBM. Treatment with bevacizumab (BEV) may increase intratumoral hypoxia. An ongoing phase 1/2 study (NCT01403610) investigates safety and activity of TH-302, an investigational hypoxia-activated prodrug, combined with BEV in patients with BEV-refractory GBM. METHODS: Single center, dose-escalation, prospective study with 2:1 randomization to TH-302 single dose of 575 mg/m2 or placebo administered pre-surgery (cohorts 1-3 only), followed by post-surgery combination therapy of BEV at 10 mg/kg and TH-302 dose escalated 240-670 mg/m2 every 2 weeks (4-week cycle) until disease progression. Following the first 5 patients in cohort 3, patients were allowed to proceed directly to TH-302/BEV combination therapy without surgery. RESULTS: Twenty three patients have been enrolled: 14 randomized in presurgery cohorts 1-3 with 9 proceeding to TH-302/BEV after surgery and 9 additional patients proceeding directly to TH-302/BEV. No grade 4 adverse events (AEs) were observed. Three grade 3 AEs in 3 patients were observed: skin ulceration at 340 mg/m2, thrombocytopenia at 670 mg/m2, and oral mucositis at 670 mg/m2. Primary TH-302-related toxicities were mucosal, but not dose limiting: rectal mucositis in 1/4 patients at 480 mg/m2 and 6/8 patients at 670 mg/m2 (all grade 1 or 2). Oral mucositis was limited. Best tumor responses in 18 evaluable patients: 1 complete response, 3 partial responses, and 9 stable disease. Median progression-free survival (PFS) was 3.1 mos (95% CI: 2.0 to 4.0 mos) and 4-month PFS was 26% (95% CI: 4% to 47%). CONCLUSIONS: The recommended phase 2 dose of TH-302 is 670 mg/m2 when combined with BEV. These preliminary data suggest potential activity of TH-302/BEV in GBM patients with poor prognosis. Dose expansion at 670 mg/m2 of TH-302 is ongoing.