Phase 1 Study Of TH-302, An Investigational Hypoxia-Targeted Drug, and Dexamethasone In Patients With Relapsed/Refractory Multiple Myeloma

In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow, suggesting that hypoxia may be a therapeutically meaningful target in this disease. TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide (Br-IPM) designed to be selectively activated in hypoxia. TH-302 exhibited anti-tumor activity in preclinical MM models in vitro and in vivo (Hu et al, Blood 2010; Chesi et al, Blood 2012), and synergism was seen when combined with the proteasome inhibitor bortezomib (Hu et al, Mol Cancer Ther 2013). Based on these findings, a Phase 1/2 study of TH-302 plus dexamethasone was initiated for patients with relapsed/refractory MM.

Eligible patients in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least 2 prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dexamethasone (dex) and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD); assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302.

As of August 2013, 13 patients have been treated: 8 males/5 females with a median age of 59 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All had previously received both bortezomib and lenalidomide/thalidomide containing regimens as well as an alkylating agent. TH-302 was dosed at 240 (n=5), 340 (n=6), and 480 (n=2) mg/m² for a median of 5 cycles (range: 1 – 18). No DLTs were reported at 240 or 340 mg/m². Two patients treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. Four patients had serious adverse events (SAEs) related to TH-302 (pneumonia (n=2), proctalgia (n=1), anemia (n=1)). Three patients continue on study after a median of 17 cycles (range: 7 – 18). Twelve patients have had efficacy evaluations: 2 patients with partial responses (PRs), 3 patients with minimal responses (MRs), and 7 patients with stable disease (SD), for a clinical benefit rate (MR or better) of 42%.

TH-302 can be administered at 340 mg/m² biweekly together with dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with a clinical benefit rate of 42% in heavily pretreated MM patients who are relapsed/refractory to both bortezomib and lenalidomide.

Ghobrial:BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees; Noxxon: Research Funding; Genzyme: Research Funding. Raje:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding. Handisides:Threshold Pharmaceuticals: Employment, Equity Ownership. Kroll:Threshold Pharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Acetylon: Equity Ownership; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson&Johnson: Membership on an entity’s Board of Directors or advisory committees.