Oprozomib, Pomalidomide, and Dexamethasone (OPomd) in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): Initial Results of a Phase 1b Study (NCT01999335)
Authors: Shah Jatin , Niesvizky Ruben , Stadtmauer Edward , Rifkin Robert M. , Berenson James , Berdeja Jesus G. , Sharman Jeff P. , Lyons Roger , Klippel Zandra , Wong Hansen , Chang Yu-Lin , Usmani Saad 
Published: October 2019

Abstract
Introduction: Oprozomib (OPZ), an oral, irreversible proteasome inhibitor, has shown activity in RRMM pts (Vij, Haematologica 2015;100[suppl 1]:abst P646; Hari, Haematologica 2015;100[suppl 1]:abst P653). Herein we present initial results of the phase 1b portion of a multicenter, phase 1b/3 study evaluating the safety and efficacy of the combination of OPZ, pomalidomide (POM), and dexamethasone (DEX) in pts with RRMM.
Methods: Pts with RRMM (≥2 prior regimens) were eligible; pts must have received ≥2 consecutive cycles of both bortezomib (BTZ) and either lenalidomide or thalidomide. Prior carfilzomib (CFZ) was allowed if CFZ was not discontinued due to an adverse event (AE). Pts received OPZ orally once-daily on days (D) 1-5 and 15-19 (ie, 5/14 schedule) or on D1, 2, 8, 9, 15, 16, 22, 23 (ie, 2/7 schedule) of 28-day cycles. Pts received POM orally on D1-21 and DEX 20 mg orally on D1, 2, 8, 9, 15, 16, 22, 23. The starting OPZ dose in the 5/14 schedule was 150 mg/day and in the 2/7 schedule was 210 mg/day; subsequent escalation was in a standard 3 + 3 dose-escalation schema. The starting POM dose for both schedules was 4 mg. If the starting dose cohorts exceeded the maximum tolerated dose (MTD) of OPZ within the OPomd regimen, POM doses were to be reduced to 3 mg or 2 mg in subsequent cohorts. OPomd was administered until disease progression or unacceptable toxicity. The primary objective of the phase 1b portion is to determine the MTD and recommended phase 3 dose (RP3D) of OPZ in the OPomd regimen and evaluate the safety and tolerability of the regimen. Secondary objectives include estimating the overall response rate (≥partial response) and clinical benefit rate (≥minimal response), and evaluating OPZ pharmacokinetics (PK).
Results: As of June 26, 2015, 31 pts were enrolled (5/14 schedule, n=4; 2/7 schedule, n=17 and n=10 for the expansion arm). This abstract will focus on the escalation portion of the study (n=21); data from the expansion cohort will be updated at the time of the meeting. In the 5/14 schedule, pts received OPZ 150 mg/day + POM 4 mg/day (n=3); or OPZ 150 mg/day + POM 2 mg/day (n=1). In the 2/7 schedule, pts received OPZ 210 mg/day + POM 4 mg/day (n=7); or OPZ 240 mg/day + POM 4 mg/day (n=10). Median age was 57 yr (5/14 schedule) and 66 yr (2/7 schedule). Pts received a median of 8 prior regimens (range, 2-22) in the 5/14 schedule and 4.5 prior regimens (range, 2-11) in the 2/7 schedule. Four pts (100%) and 8 pts (47%) in the 5/14 and 2/7 schedules, respectively, received CFZ in their last prior regimen. In the 5/14 and 2/7 schedules, 50% and 76% of pts were BTZ-refractory, 25% and 41% were CFZ-refractory, and 100% and 82% were refractory to an immunomodulatory agent, respectively. At the time of data cutoff, pts in the 5/14 and 2/7 schedules had been on treatment for a median duration of 9.2 wk (range, 3.3-28.0) and 15.6 wk (range, 3.3-40.3) for all study drugs, respectively. For OPZ specifically, the median duration of treatment was 9.0 wk (range, 2.7-27.6) and 15.6 wk (range, 3.3-40.3) in the 5/14 and 2/7 schedules, respectively. Three dose-limiting toxicities (DLTs) were reported in 2 pts in the 5/14 schedule (OPZ 150 mg/day + POM 4 mg/day + DEX 20 mg/day cohort): 1 pt had grade (Gr) 3 mucositis and 1 pt had Gr 3 abdominal distention and Gr 3 impaired cognitive function. One DLT occurred in the 2/7 schedule: 1 pt had Gr 3 gastric hemorrhage with severe erosive gastritis identified in endoscopy (OPZ 210 mg/day + POM 4 mg/day + DEX 20 mg/day cohort). The most common AEs of any Gr and of Gr ≥3 are shown in Table 1. One pt in the 5/14 schedule (25%) and 2 pts (12%) in the 2/7 schedule had a dose withdrawn due to an AE. No pts died on study. In the 5/14 schedule, a partial response or better was reported in 2 pts (50%) in the 5/14 schedule and in 10 pts (59%) in the 2/7 schedule (Table 2). Considering current measures of variability and sample size, the PK of OPZ, when given in combination with POM and DEX, were generally consistent with previous OPZ studies.
Conclusions: Initial results from this ongoing phase 1b study suggest that the combination of OPomd has encouraging anti-myeloma activity and is generally well tolerated; the most common Gr ≥3 AEs observed in the study were anemia and diarrhea (n=4 each; 24%) in the 2/7 schedule. No Gr ≥3 AE occurred in more than 1 pt in the 5/14 schedule. While the MTD was not defined on either schedule, the 2/7 schedule at 210 mg dose of OPZ was chosen for the expansion cohort based on the safety and efficacy data available.

Disclosures
Shah: Celgene: 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, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Array: Research Funding; BMS: Research Funding. Niesvizky:Celgene: Consultancy, Speakers Bureau. Stadtmauer:Amgen/Onyx Pharmaceuticals: Consultancy, Research Funding. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: 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. Berdeja:Onyx: Research Funding; Celgene: Research Funding; Curis: Research Funding; Novartis: Research Funding; BMS: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; MEI: Research Funding; Array: Research Funding; Takeda: Research Funding; Abbvie: Research Funding. Sharman:TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Calistoga: Honoraria. Lyons:Amgen: Consultancy, Honoraria; Insyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Klippel:Amgen Inc.: Employment, Equity Ownership. Wong:Amgen/Onyx: Employment, Equity Ownership. Chang:Onyx: Employment. Usmani:Onyx: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria; Janssen: Research Funding.