A Phase 1b Study of Oprozomib with Dexamethasone or Pomalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Hari Parameswaran , Schroeder Mark A. , Berenson James R , Jakubowiak Andrzej , Kaufman Jonathan L , Voorhees Peter M. , Fujii Hisaki , Yang Zhao , Galimi Francesco , Shain Kenneth H. 
Published: October 2019

Abstract
Introduction: Oprozomib is a selective oral tripeptide epoxyketone inhibitor of the chymotrypsin-like subunit of the constitutive proteasome and immunoproteasome. This phase 1b study evaluated the safety and tolerability of two new formulations of oprozomib in combination with dexamethasone (Odex) or pomalidomide and dexamethasone (OPomD) in patients with relapsed or refractory multiple myeloma (RRMM).
Methods: Adult patients with RRMM who had received at least 2 prior lines of therapy and whose prior treatment included both lenalidomide and a proteasome inhibitor were eligible for inclusion. Patients received either immediate-release (IR) or extended-release gastroretentive (GR) oprozomib, orally, in combination with dexamethasone (20 mg) alone or pomalidomide (4 mg) and dexamethasone (20 mg) in 4-week cycles. Oprozomib was given according to a 2/7 schedule on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 4-week cycle. In part 1 of the study, patients received Odex with either IR oprozomib at 150 mg/day or GR oprozomib at 150 mg/day. In part 2 of the study, patients received OPomD at increasing dose levels. Dosing for the IR formulation began at 150 mg/day and could be increased to 300 mg/day in increments of 25 mg as needed; at least one cohort could be enrolled at each dose level of oprozomib. Dosing for the GR formulation was determined based on the efficacy and safety data observed in the initial IR dose escalation and was at least one dose level lower than the highest dose tested of the IR formulation. The primary objectives of the study were to identify the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of the OPomD formulations.
Results: Overall, 34 patients were assessed at the time of this analysis. Baseline patient demographics and disease characteristics are shown in Table 1. Fourteen patients (41%) received prior carfilzomib, and 10 of these were carfilzomib-refractory; 27 patients (79%) received prior bortezomib and 14 were bortezomib-refractory. Patients were enrolled into 6 cohorts and received either IR 150 mg/day (n=5) or GR 150 mg/day (n=8) Odex, or IR 150 mg/day (n=4), IR 200 mg/day (n=8), IR 225 mg/day (n=5), or GR 150 mg/day (n=4) OPomD. Median (interquartile range) number of cycles of oprozomib received for each cohort was 2.0 (1.0-11.0), 3.5 (1.5-4.0), 6.5 (2.5-9.5), 4.5 (3.0-5.5), 1.0 (1.0-1.0), and 2.0 (1.5-2.0), respectively. Three patients experienced dose-limiting toxicities (IR 150 mg/day OPomD, increased lipase; IR 200 mg/day OPomD, acute kidney injury; GR 150 mg/day OPomD, febrile neutropenia). At the time of this analysis the MTD was not yet reached for either the IR or GR formulation. Most patients (97%) experienced ≥1 treatment-emergent adverse event (AE) and 23 (68%) experienced ≥1 treatment-emergent grade ≥3 AE. AEs that occurred in ≥50% of patients in any cohort are listed in Table 2; the most common overall were nausea (62% any grade; 3% grade ≥3), diarrhea (50% any grade; 6% grade ≥3), and vomiting (47% any grade; 6% grade ≥3). Four patients (12%) experienced treatment-emergent AEs leading to discontinuation of study drug; no fatal AEs occurred. Seven patients who received OPomD had an objective response at the time of this analysis (IR 150 mg/day, n=1 [33%], median duration of response [DOR]=169 days; IR 200 mg/day, n=6 [67%], median DOR=86.5 days; DOR assessments ongoing). Of the seven patients with an objective response, six had a partial response (IR 150 mg/day and IR 200 mg/day) and one had a very good partial response (IR 200 mg/day). Progression-free survival data were not yet mature. In total, 16 of 34 patients continue to receive oprozomib therapy. The results reported are based on preliminary data available at the time of analysis. The study is ongoing and updated results will be provided at the meeting.
Conclusion: Results from this study showed that treatment with OPomD had manageable toxicity in patients with RRMM. The most common AEs observed were gastrointestinal disorders, and most of these were grade 1-2 with no gastrointestinal bleeding reported. Furthermore, OPomD therapy showed promising efficacy, with an objective response rate of 67% for patients in the IR 200-mg/day cohort.

Disclosures
Hari: Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berenson:Amgen Inc.: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman:BMS: Consultancy; Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy. Voorhees:Amgen Inc.: Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TeneoBio: 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; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC. Fujii:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Galimi:Amgen Inc.: Employment, Equity Ownership.