The oral proteasome inhibitor (PI) oprozomib demonstrated promising activity in patients with relapsed multiple myeloma and Waldenström macroglobulinemia in a phase 1b/2 study published recently in Clinical Cancer Research.

“Because of the limitations and challenges of the 3 PIs currently approved for multiple myeloma treatment, there is a need for additional PIs that are effective, tolerable, and convenient,” researchers wrote. 

This study evaluated oprozomib, an oral tripeptide epoxyketone PI that is structurally similar to carfilzomib and binds selectively and irreversibly to the proteasome. The drug was administered once daily on days 1, 2, 8, and 9 (2/7 schedule) or days 1 to 5 (5/14 schedule) of a 14-day cycle. 

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In the phase 1b portion of the study, maximum tolerated dose, safety and tolerability were evaluated. The study included 71 patients with relapsed multiple myeloma and Waldenström macroglobulinemia. During this phase, all patients with myeloma on a 2/7 schedule received tablets. Among patients on the 5/14 schedule, 20 patients received tablets and 11 received oprozomib powder in capsule (PIC). 

The dose was initiated at 120 mg per day and escalated by 30-mg increments up to 210 mg. 

The determined maximum tolerated doses were 300 mg per day for the 2/7 schedule and 240 mg per day for the 5/14 schedule. Median duration of treatment for patients with myeloma was 11.4 weeks for the 2/7 schedule (240/300 mg per day), 5.4 weeks for the 5/14 schedule (240 mg per day), and 10.1 weeks for the 5/14 schedule (150/180 mg per day). 

For patients with WM, the median treatment duration was 34.6 weeks (2/7 schedule 240/300 mg per day) and 8.1 weeks (5/14 schedule, 240 mg per day). 

Gastrointestinal and hematologic adverse events (AEs) were the most commonly occurring grade 3 or worse adverse events. 

After 3 AE-related deaths occurred in the phase 2 portion, the researchers initiated enrollment into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). 

“The step-up dosing regimen addressed the higher than desired gastrointestinal toxicity and discontinuation rates observed in the early phase 2 cohorts in which patients were administered oprozomib 240 mg/day on the 5/14 schedule,” the researchers wrote. “In our study, step-up dosing appeared to be better tolerated than continuous dosing, possibly because step-up dosing allowed oprozomib levels to rise gradually.”

The phase 2 portion included 135 patients (102 with myeloma). The overall response rate for 95 eligible patients with myeloma were 41.0%, 28.1%, and 25.0% for the 240/300-mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. Among patients with WM, the ORRs were 71.4% for the 2/7 schedule and 47.1% for the 5/14 schedule. 

“With the caveat that cross-trial comparisons should be interpreted with caution, the ORRs (defined as partial response or better) observed in the phase 2 portion of this study for patients with multiple myeloma (25.0%–41.0%) were similar to or higher than that of phase 1–3 trials of other PIs administered as single agents in the relapsed setting,” the researchers wrote. “Higher ORRs with oprozomib are likely to be observed in future studies with larger Waldenström macroglobulinemia patient populations, and by improving drug formulations to prevent AE-related discontinuations.”

Reference

Ghobrial IM, Vij R, Siegel D, et al. A phase Ib/II study of oprozomib in patients with advanced multiple myeloma and Waldenström macroglobulinemia.[published online July 10, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-3728