Final Results from a Multicenter, Open-Label, Dose-Escalation Phase 1b/2 Study of Single-Agent Oprozomib in Patients with Hematologic Malignancies
Authors: Ghobrial Irene M. , Savona Michael R. , Vij Ravi , Siegel David S. , Badros Ashraf , Kaufman Jonathan L. , Raje Noopur , Jakubowiak Andrzej , Obreja Mihaela , Berdeja Jesus G. 
Published: October 2019

Abstract
Background: Oprozomib (OPZ) is an oral proteasome inhibitor. This phase 1b/2 study (NCT01416428) is evaluating single-agent OPZ in patients with relapsed hematologic malignancies, including those with multiple myeloma (MM) and Waldenström macroglobulinemia (WM). In the phase 1b portion of the study, the maximum tolerated dose (MTD) of single-agent OPZ was 300 mg/day when administered on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or 240 mg/day when administered on days 1-5 of a 14-day cycle (5/14 schedule) (Vij et al. Blood.2014;124:abstr 34). Here, we present final results from the phase 2 portion of the study.
Methods: Adults with relapsed MM or WM (≥1 prior therapy) were eligible for the phase 2 portion of the study. The primary objective of the phase 2 portion was to determine the overall response rate (ORR).
During phase 2, patients on the 5/14 schedule received OPZ at the MTD of 240 mg/day, or in a step-up dosing scheme where patients received 150 mg/day in cycle 1, and stepped-up to a target dose of 180 mg/day thereafter (ie, 150/180 mg/day). Patients on the 2/7 schedule received OPZ in a step-up dosing scheme of 240/300 mg/day. All patients received premedication with a 5-hydroxytryptamine-3 inhibitor and dexamethasone 4 mg.
Results: During phase 2, patients were initially treated on the 5/14 schedule at the MTD of 240 mg/day (MM, n=27; WM, n=17). Three patients with MM died on study: 2 due to treatment-related gastrointestinal (GI) hemorrhage and 1 due to progressive disease. The study protocol was then amended to test alternative regimens and lower doses, and patients were subsequently enrolled on the 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). The phase 2 portion enrolled 56 patients on the 2/7 step-up dosing schedule (MM, n=41; WM, n=15) and 34 patients on the 5/14 step-up dosing schedule (all MM).
Median ages in MM patients were 65 years (2/7, 240/300 mg/day), 64.5 years (5/14, 150/180 mg/day), and 63 years (5/14, 240 mg/day); median ages in WM patients were 65 years (2/7, 240/300 mg/day) and 62 years (5/14, 240 mg/day). Median numbers of prior regimens were 4, 3.5, 5, 2, and 3 in these cohorts, respectively. Among MM patients, 68% were bortezomib (BTZ)-refractory, 37% were carfilzomib (CFZ)-refractory, 75% were lenalidomide-refractory, 45% were pomalidomide-refractory, and 71% had received prior transplant. Median treatment durations were 11.4 weeks (MM, 2/7 schedule, 240/300 mg/day), 10.1 weeks (MM, 5/14 schedule, 150/180 mg/day), 5.4 weeks (MM, 5/14 schedule, 240 mg/day), 34.6 weeks (WM, 2/7 schedule, 240/300 mg/day), and 8.1 weeks (WM, 5/14 schedule, 240 mg/day).
Across all cohorts, the most common grade ≥3 adverse events (AEs) included diarrhea, anemia, thrombocytopenia, fatigue, nausea, and vomiting (Table 1). Among patients with MM, the proportions of patients who discontinued treatment due to AEs were 44%, 12%, and 48% in the 2/7, 240/300 mg/day; 5/14, 150/180 mg/day; and 5/14, 240 mg/day cohorts, respectively. Among patients with WM, the proportions of patients who discontinued treatment due to AEs were 20% and 47% in the 2/7 and 5/14 schedules, respectively. No on-study deaths occurred in the 2/7 schedule nor in the 5/14 step-up dosing cohorts.
Efficacy outcomes are shown in Table 2. Among response-eligible patients with MM, ORRs were 34%, 22%, and 25% in the 2/7, 240/300 mg/day (n=38); 5/14, 150/180 mg/day (n=32); and 5/14, 240 mg/day (n=24) cohorts, respectively. Among BTZ-refractory patients with MM, ORRs were 28% and 17% on the 2/7 (n=29) and 5/14 (n=24) schedules, respectively; among CFZ-refractory patients, ORRs were 8% and 10% on the 2/7 (n=13) and 5/14 (n=21) schedules. For response-eligible patients with WM, ORRs were 71% and 47% on the 2/7 (n=14) and 5/14 (n=17) schedules.
Conclusions: Single-agent OPZ appears to have promising activity in patients with relapsed MM or WM, with durable responses overall and responses observed in those refractory to BTZ or CFZ. GI events (primarily diarrhea) were among the most common grade ≥3 AEs with single-agent OPZ. Further exploration of OPZ therapeutic effect is planned with modified formulations and optimized schedule and dosing administration.

Disclosures
Ghobrial: Noxxon: Honoraria; Novartis: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Vij:Amgen: Honoraria, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Research Funding. Siegel:Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Kaufman:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding. 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. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Obreja:Amgen: Employment. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.