A Phase 1/2 Study of evofosfamide, A Hypoxia-Activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma

Purpose: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM). Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxia. A phase 1/2 study investigating evofosfamide in combination with dexamethasone (EvoD) and in combination with bortezomib and dexamethasone (EvoBorD) in relapsed/refractory MM. Experimental Design: 59 patients initiated therapy, 31 received EvoD and 28 received EvoBorD. Pts were heavily pre-treated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The maximum tolerated dose (MTD), treatment toxicity, and efficacy were determined. Results: The MTD was established at 340 mg/m² Evo+D with dose limiting mucositis at higher doses. For EVOBorD, no patient had a dose limiting toxicity and the recommended phase 2 dose was established at 340 mg/m². The most common ≥ Gr 3 adverse events were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients) and leukopenia (9 patients). Skin toxicity was reported in 42 (71%). Responses included 1 VGPR, 3 PR, 2 MR, 20 SD and 4 PD for EvoD and 1 CR, 2 PR, 1 MR, 18 SD and 5 PD for EvoBorD. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months. Conclusions: Evofosfamide can be administered at 340 mg/m² twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pre-treated relapsed refractory MM.

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