Final Results of a Phase 1/2 Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of Evofosfamide, a Hypoxia-Activated Prodrug, and Dexamethasone with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma
Authors: Laubach Jacob P. , Raje Noopur , Yee Andrew J. , Armand Philippe , Schlossman Robert L. , Rosenblatt Jacalyn , Martin Michael G. , Reynolds Craig , Shain Kenneth H. , Zackon Ira , Stampleman Laura V. , Lai Emily , Caola Aaron M. , Cappuccio Joseph M. , Rivotto Bradley , Reyes Kaitlen , Savell Alexandra , Henrick Patrick , Pearce Tillman , Handisides Damian , Kroll Stew , Anderson Kenneth C. , Richardson Paul G. , Ghobrial Irene M. 
Published: October 2019

Abstract
Purpose: This phase 1/2 study was conducted to determine the maximum tolerated dose (MTD), safety, tolerability, and clinical activity of the hypoxia-activated prodrug evofosfamide (TH-302) and dexamethasone with or without bortezomib in relapsed/refractory multiple myeloma.
Patients & Methods: Patients were enrolled to stage A (evofosfamide + dexamethasone) followed by stage B (evofosfamide + bortezomib + dexamethasone). Stage A enrollment began in March 2012 and ended in May 2014. In total 34 patients were enrolled to stage A, with 31 patients being treated. Stage B enrollment began in June 2014 and ended in July 2015. In total 28 patients were enrolled and treated on stage B. Patients enrolled on study were diagnosed with relapsed/ refractory multiple myeloma (RRMM), had adequate hepatic, renal, and hematologic function, as well as an ECOG performance status of ≤2, and had all received at least 2 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. In stage B, patients previously receiving bortezomib must not have discontinued due to toxicity. Patients must have had measureable disease as determined by the International Working Group (IMWG) criteria. In stage A, evofosfamide was administered IV in conjunction with a fixed oral dose of 40 mg dexamethasone on Days 1, 4, 8 and 11 of a 21-day cycle. In stage B, evofosfamide was administered in conjunction with a fixed oral dose of 40 mg dexamethasone and a fixed IV or SC dose of 1.3 mg/m2 bortezomib. Stage A dose escalation began at a dose of 240 mg/m2 evofosfamide and increased stepwise in a 3+3 design until reaching the MTD of 480 mg/m2. The recommended phase 2 dose (RP2D) was set at 340 mg/m2 and a dose expansion cohort of 15 treated patients were treated at the RP2D. Stage B dose escalation began at a dose of 240 mg/m2 and concluded at the 340 mg/m2 RP2D of stage A. There were no DLTs observed in this cohort. A total of 24 patients were treated at the RP2D.
Results: Of the 31 patients treated on stage A, the median age was 65, with a range of 53-86. The median number of prior treatments was 6 (range: 2-13). Of the 28 patients treated on stage B, the median age was 62, with a range of 45-83. The median number of prior treatments was 8 (range: 3 - 16). All patients had prior bortezomib exposure with a median number of bortezomib containing regimens in stage B of 3 (range: 1-6). The most common stage A grade 3/4 events were anemia (36%), neutropenia (32%), thrombocytopenia (39%), leukopenia (23%), cellulitis (10%) and pneumonia (10%). Four pts (13%) discontinued due to an adverse event. The most common Arm B grade 3/4 events were thrombocytopenia (61%), neutropenia (32%), anemia (25%), leukopenia (18%) and pneumonia (14%). Two patients (7%) discontinued due to an adverse event. Of the 31 patients evaluable for response in stage A, 4 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 19%. Twenty patients (65%) in stage A had stable Disease. Of the 28 patients evaluable for response in stage B, 1 Complete Response, 2 Partial Responses and 2 Minimal Responses were reported for a clinical benefit rate of 18%. Eighteen patients (64%) in stage B had Stable Disease.
Conclusion: A 340 mg/m2 twice a week dose of the hypoxia- activated agent evofosfamide was established as the recommended Phase 2 dose when combined with dexamethasone with or without bortezomib. Clinical activity was noted along with a majority of patients having stable disease or better even in this heavily pre-treated refractory population of MM. The use of hypoxia-activated agents holds promise as a novel therapeutic target in MM.

Disclosures
Raje: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Armand:Pfizer: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Merck: Consultancy, Research Funding. Rosenblatt:BMS: Research Funding; Astex: Research Funding; DCPrime: Research Funding. Shain:Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Anderson:Oncopep: Other: Scientific Founder; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Other: Scientific Founder; Sonofi Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria; Noxxon: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding.