A Phase 1/2 Trial of TH-302 and Dexamethasone without or with Bortezomib (TBorD) in Patients with Relapsed/Refractory Multiple Myeloma

Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxic conditions. TH-302 has demonstrated anti-myeloma activity in preclinical models both in vitro and in vivo, as well as synergistic cytotoxic activity with bortezomib (Bor) in vitro. An ongoing Phase 1/2 study (NCT01522872) investigates TH-302 with dexamethasone (dex) without Bor or with Bor (TBorD) in patients (pts) with relapsed/refractory multiple myeloma (RR MM). The maximum-tolerated dose (MTD) of TH-302 plus dex was previously established at 340 mg/m². We report preliminary results from pts treated at the MTD of TH-302 plus dex; enrollment in the TBorD arm is ongoing.

Methods: The Phase 1/2 open-label multicenter study investigates IV TH-302 (240-480 mg/m²) plus PO dex (40 mg) with or without Bor (1.3 mg/m²) on Days 1, 4, 8 and 11 of a 21-day cycle. At the MTDs, Simon two-stage designs are implemented to pursue a regimen of TH-302 plus dex if ≥25% response rate or discontinue if ≤5% (90% power, 10% alpha), and pursue TBorD if ≥50% response rate or discontinue if ≤25% (85% power, 10% alpha). Treatment at the MTD of TH-302 plus dex, and establishment of the MTD of TH-302 in TBorD, is ongoing.

Results: 24 pts (19 male, 5 female) with median age 65 years (range: 53 – 86) were enrolled at the 340 mg/m² MTD of the TH-302 plus dex biweekly regimen. Ten pts had 18 severe adverse events (SAEs), of which 9 were related to TH-302, including 3 pts with cellulitis and 2 pts with pneumonia. Of 17 pts assessable for response at the time of abstract submission, 3 pts achieved a partial response (PR) and 2 pts achieved a minimal response (MR) for an overall response rate of 18% (PR) and a clinical benefit rate of 29% (PR+MR). Nine pts achieved stable disease and 3 pts had progressive disease. Eight pts are undergoing treatment; 16 pts discontinued: progressive disease (10), subject decision (4), AE (1) and alternative therapy (1). The initial dose escalation with TBorD has been completed at 240 mg/m² TH-302, with enrollment ongoing at 340 mg/m² TH-302.

Conclusions: TH-302 can be administered at 340 mg/m² biweekly with dex. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from the complete cohort of pts treated with dex and initial patients treated with TBorD will be updated and presented at the meeting.