A Phase Ib/II Study of Oprozomib in Patients with Advanced Multiple Myeloma and Waldenström Macroglobulinemia

Clin Cancer Res. 2019 Aug 15;25(16):4907-4916. doi: 10.1158/1078-0432.CCR-18-3728. Epub 2019 May 29.

Abstract

Purpose: The oral proteasome inhibitor oprozomib has shown preclinical antitumor activity. Here, we report phase Ib/II study results investigating single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.

Patients and methods: The primary objectives were to determine the MTD, safety, and tolerability of oprozomib (phase Ib) as well as overall response rate (ORR; phase II). Oprozomib 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.

Results: In patients with multiple myeloma or Waldenström macroglobulinemia (n = 71), the determined MTDs were 300 mg/day (2/7 schedule) and 240 mg/day (5/14 schedule). Median oprozomib treatment duration for patients with multiple myeloma was 11.4 weeks (2/7 schedule, 240/300 mg/day), 5.4 weeks (5/14, 240 mg/day), and 10.1 weeks (5/14, 150/180 mg/day). For patients with Waldenström macroglobulinemia, these values were 34.6 weeks (2/7 schedule, 240/300 mg/day) and 8.1 weeks (5/14 schedule, 240 mg/day). The most common grade ≥3 adverse events (AE) in phase Ib included gastrointestinal and hematologic AEs. Three AE-related deaths in phase II prompted enrollment into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). In phase II, ORRs in 95 response-eligible multiple myeloma patients were 41.0%, 28.1%, and 25.0% in the 2/7, 240/300-mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. ORRs in 31 response-eligible Waldenström macroglobulinemia patients were 71.4% and 47.1% for the 2/7 and 5/14 cohorts, respectively.

Conclusions: This study demonstrated promising efficacy of single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma / diagnosis
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / mortality
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Oligopeptides / administration & dosage
  • Oligopeptides / adverse effects
  • Oligopeptides / therapeutic use*
  • Proteasome Inhibitors / administration & dosage
  • Proteasome Inhibitors / adverse effects
  • Proteasome Inhibitors / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome
  • Waldenstrom Macroglobulinemia / diagnosis
  • Waldenstrom Macroglobulinemia / drug therapy*

Substances

  • ONX 0912
  • Oligopeptides
  • Proteasome Inhibitors