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).
2015; Lippincott Williams & Wilkins; Volume: 33; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2015.33.15_suppl.8579
ISSN1527-7755
AutoresJacob P. Laubach, Noopur Raje, Andrew J. Yee, Philippe Armand, Robert Schlossman, Jacalyn Rosenblatt, Jacquelyn Hedlund, Michael G. Martin, Craig H. Reynolds, Kenneth H. Shain, Ira Zackon, Laura Stampleman, Erica N Boswell, Stacey Chuma, Rebecca Liguori, Damian Handisides, Stew Kroll, Kenneth C. Anderson, Paul G. Richardson, Irene M. Ghobrial,
Tópico(s)Multiple Myeloma Research and Treatments
Resumo8579 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) have been reported (3 at 240 mg/m2 EVO and 6 at 340 mg/m2 EVO). Pts were heavily pre-treated; median number of prior therapies was 8 (4 – 12). Median age was 57 years (45 – 68). All had previously received Bor and lenalidomide or thalidomide. No pt had a dose limiting toxicity and the recommended phase 2 dose (RP2D) was established at 340 mg/m2 EVO. The most common ≥ Gr 3 adverse events (AEs) were thrombocytopenia (5 pts), lymphopenia (2 pts), leukopenia (2 pts) and anemia (2 pts). Limited skin toxicity has been observed (2 pts, grade 2 rash or skin lesions). Four pts had SAEs; one SAE of thrombocytopenia was related to EVO. Seven pts discontinued for progressive disease; no pts have discontinued due to an AE. IMWG assessments were 1 CR, 2 PR, 4 SD and 2 PD (1 CR and 2 PRs out of 6 pts at 340 mg/m2 EVO). Two pts with a CR and PR continue on study. To date, 17 of 24 pts have been enrolled to evaluate safety and efficacy at the RP2D. Conclusions: EVO can be administered at 340 mg/m2 twice a week with Bor and D. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from pts treated at the RP2D will be updated and presented at the meeting. Clinical trial information: NCT01522872.
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