Preliminary safety and efficacy of evofosfamide (TH-302), an investigational hypoxia-activated prodrug, combined with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma (RR MM).

8579 Background: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM) (Colla, Leukemia 2010). Evofosfamide (EVO; formerly TH-302) is a novel 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxia and is investigated in multiple Phase 1-3 trials. Synergistic induction of apoptosis in MM cells by EVO and bortezomib (Bor) was shown in vivo and in vitro (Hu et al, Mol Cancer Ther2013). An ongoing phase 1/2 study investigates EVO in combination with Bor and dexamethasone (D) in RR MM (NCT01522872). Methods: This phase 1/2 open-label multicenter study investigates IV EVO (240-480 mg/m²), IV or SC Bor (1.3 mg/m2), plus PO D (40 mg) on Days 1, 4, 8 and 11 of a 21-day cycle. At the maximum tolerated dose, a Simon two-stage optimal design was implemented to pursue a regimen with ≥ 50% response rate or discontinue if ≤ 25% (85% power, 10% alpha). Results: Nine patients (pts; 4 male, 5 female) ...