Efficacy and safety results from a phase 1b/2, multicenter, open-label study of oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. (August 2019)

• Record Type: Journal Article
• Authors: Hari, Parameswaran; Paba-Prada, Claudia E.; Voorhees, Peter M.; Frye, John; Chang, Yu-Lin; Moreau, Philippe; Zonder, Jeffrey; Boccia, Ralph; Shain, Kenneth H.
• Is Part Of: Leukemia research. Volume 83(2019)
• Publication Date: 2019-08
• Subjects: AE adverse event -- AUClast area under the plasma concentration-time curve to the last measurable concentration -- CBR clinical benefit rate -- CI confidence interval -- Cmax maximum observed concentration -- CV% percent of coefficient of variation -- DLT dose-limiting toxicity -- ECOG Eastern Cooperative Oncology Group -- ER extended release -- GI gastrointestinal -- MM multiple myeloma -- MTD maximum tolerated dose -- NE not estimable -- ORR overall response rate -- PFS progression-free survival -- PK pharmacokinetics -- PR partial response -- RP2D recommended phase 2 dose -- RRMM relapsed or refractory MM -- t1/2 terminal half-life -- Tmax time to maximum concentration; Oprozomib -- Oral proteasome inhibitor -- Dexamethasone -- Multiple myeloma -- Maximum tolerated dose; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2019.106172
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Efficacy and safety w/ oprozomib-dexamethasone in RRMM patients were investigated. ORR for the 2/7 schedule was 58.7% overall and 46.4% for bor-refractory patients. Limitations including GI toxicities and intrapatient PK variability halted study. New formulation of oprozomib w/ improved gastrointestinal tolerability is warranted. Abstract: Oprozomib is an oral proteasome inhibitor with activity in multiple myeloma (MM). Our phase 1b/2 study examined the safety and efficacy of oprozomib with dexamethasone in patients with relapsed and refractory MM. Oprozomib was administered with a 5/14 or 2/7 schedule with dexamethasone. Phase 1b primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of oprozomib; phase 2 primary objectives were to determine overall response rate (ORR) and safety/tolerability of the RP2D. Between July 2, 2013, and August 29, 2016, data were available on 65 enrolled patients (5/14 schedule, n = 19; 2/7 schedule, n = 46). In phase 1b, MTD was 180 mg (5/14 schedule) and not reached (2/7 schedule); RP2D was 300 mg (2/7 schedule). In phases 1b and 2, ORR across dosing cohorts (210–330 mg) for the 2/7 schedule was 58.7% overall and 46.4% for bortezomib-refractory patients (n = 28). All patients reported ≥1 treatment-emergent adverse event (AE); the most common AEs were gastrointestinal. Grade ≥3 AEs occurred in 78.9% and 82.6% of patients on the 5/14 and 2/7 schedules, respectively. The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved.