Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study
Authors: Ghobrial Irene M. , Kaufman Jonathan L. , Siegel David S. , Vij Ravi , Badros Ashraf , Neuman Linda , Wong Hansen , Anderl Janet , Savona Michael 
Published: October 2019

Abstract

Background
Oprozomib (OPZ), a structural analog of carfilzomib (CFZ), is an oral, second-generation epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings have shown that modified-release OPZ tablets have acceptable safety and tolerability and promising antitumor activity in pts with hematologic malignancies (HM) (Kaufman JL, et al. EHA 2013, P233). Updated results are presented herein.

Methods
This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who relapsed after failing ≥1 line of therapy. The primary objectives are to determine the safety profile and maximum tolerated dose (MTD) of OPZ. Secondary end points include response, pharmacokinetics, and pharmacodynamics. OPZ dose escalation began at 150 mg/d. Dose levels are being increased in 30-mg increments; there is no maximal planned dose. Modified-release OPZ tablets are being administered once daily on Days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on Days 1–5 of a 14-day cycle (5/14 schedule). Peripheral blood mononuclear cells (PBMC) and whole blood (WB) samples are being collected for assessment of proteasome inhibition (PI).

Results
As of July 1, 2013, 42 pts were enrolled, including 15 multiple myeloma (MM) and 4 Waldenström's macroglobulinemia (WM) pts on the 2/7 schedule and 15 MM and 8 WM pts on the 5/14 schedule. Median pt age was 62.0 and 64.0 years (2/7 and 5/14 schedule, respectively). Two-thirds (67%) of pts had prior bortezomib (BTZ) exposure; 43% were refractory to a prior BTZ-containing regimen. Median treatment duration for the 2/7 and 5/14 schedule was 11.3 weeks and 8.7 weeks, respectively. There were 2 dose-limiting toxicities (renal failure [180 mg/d] and tumor lysis syndrome [240 mg/d]; both occurred on the 5/14 schedule). The most common grade 1–2 adverse events (AEs; ≥5 pts) are reported in Table 1. The most common grade 3–4 AEs (≥2 pts) included diarrhea (n=9); anemia, nausea, and neutropenia (n=4 each); hypophosphatemia, thrombocytopenia, and vomiting (n=3 each); and dehydration and fatigue (n=2 each) (Table 2). Two pts experienced grade 1 peripheral neuropathy (PN); both reported PN grade 2 at baseline. No new-onset or worsening of PN was reported. Thirteen pts had their treatments held or delayed; 6 had their dosage reduced at least once. Eleven pts discontinued treatment. Apparent dose-dependent increases in the Day 1 plasma area under the concentration time curve and maximum concentration (Cmax) were observed (150–300 mg/d). The median time to Cmax was 2 hr and the terminal half-life was approximately 0.5–1.5 hr. Pts receiving 240-mg/d OPZ achieved depth and duration of PI that is similar to CFZ (20/27 mg/m2). In WB, ≥90% inhibition of the primary chymotrypsin-like activity was achieved 4 hr following OPZ administration; this inhibition was sustained through Cycle 2. In PBMCs, ≥80% inhibition was observed on the first day of Cycle 1 and showed minimal recovery before dosing on day 1 of Cycle 2. OPZ administration also inhibited the secondary caspase-like and trypsin-like sites of the immunoproteasome (LMP2 and MECL1, respectively). The profile of OPZ target inhibition is similar to previous reports with CFZ. Thirteen MM and 5 WM pts on the 5/14 schedule were included in the response evaluation. The clinical benefit response rate (CBR) was 23.1% (MM) and 80.0% (WM). In pts with MM, 1 (150 mg/d) had a very good partial response, 2 (210 mg/d) had a partial response (PR), 6 (150–240 mg/d) had stable disease (SD), 1 (150 mg/d) had progressive disease (PD), and 3 were not evaluable for response. In WM pts, 4 (150–210 mg/d) had a PR and 1 (180 mg/d) had SD. In 12 MM and 3 WM pts included in the response evaluation (2/7 schedule), the CBR was 16.7% (MM) and 0% (WM). Two MM pts (150–180 mg/d) had a minimal response (MR); 10 MM (150–300 mg/d) and 3 WM (180–240 mg/d) pts had SD. In 14 pts with MM or WM who were refractory to BTZ and eligible for assessment, 3 had a PR, 1 had a MR, 9 had SD, and 1 had PD.

Conclusion
Once-daily modified release OPZ tablets continue to have acceptable safety and promising antitumor activity in MM and WM pts. The most common grade 3 AE was diarrhea; grade 4 AEs were infrequent. No grade ≥2 PN was reported in pts with baseline PN; no new-onset or worsening of PN was reported. Dose escalation is continuing in the 2/7 (300 mg/d) and 5/14 (270 mg/d) dosing schedules. The phase 2 study will begin once the MTD is reached. Updated data will be presented at the meeting.

Disclosures:
Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi (Genzyme): Research Funding; Noxxon: Research Funding. Kaufman:Jansenn: Consultancy; Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy; Merck: Research Funding. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vij:BMS: Honoraria; Lilly: Honoraria; Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Speakers Bureau. Neuman:Onyx: Employment, Equity Ownership. Wong:Onyx: Employment, Equity Ownership, Patents & Royalties, Research Funding. Anderl:Onyx: Employment, Equity Ownership.