San Francisco, CA—The oral antimyeloma proteasome inhibitor oprozomib, given as a single agent in a dose-escalation study, “showed promising antitumor activity,” which included responses even in patients with carfilzomib-refractory multiple myeloma, according to Ravi Vij, MD, of Washington University in St Louis, MO.
Oprozomib binds selectively and irreversibly to its target, resulting in sustained cancer-cell inhibition.
At ASH 2014, Dr Vij presented data from an ongoing multicenter open-label phase 1b/2 study of 129 patients with hematologic malignancies, including 87 patients with relapsed and/or refractory multiple myeloma. “The majority of patients had seen bortezomib and carfilzomib, and quite a few were refractory to both these drugs,” he noted.
Patients received oprozomib in various schedules and dose levels in 2-week cycles. During the phase 1b of the study, the formulation of oprozomib was changed from powder in a capsule to an extended-release tablet; in phase 2, step-up dosing was introduced. These amendments appeared to improve the drug’s tolerability.
Clinical Benefit of 50%
In the phase 1b cohort of patients receiving 150 to 330 mg daily for 2 of every 7 days (2/7 schedule), the objective response rate was 31.3% and the clinical benefit rate was 50%. In the patients in the phase 1b/2 of the trial who received 150- to 270-mg daily for 5 of 14 days (5/14 schedule), the response rate was 23.3% and the clinical benefit rate was 32.6%.
Of note, these response rates were observed before the step-up dosing schedule was initiated. The response data were not presented for the step-up cohorts, because of limited treatment exposure (approximately 7 weeks).
Responses were achieved by 18.2% of patients with carfilzomib-refractory disease, Dr Vij added. The recommended phase 2 dose and schedules were the 2/7 step-up schedule at 240 to 300 mg daily and the 5/14 step-up schedule at 150 to 180 mg daily.
Improved Tolerability
In the cohorts that did not benefit from step-up dosing, the most common grade ≥3 nonhematologic adverse events were diarrhea, nausea, and vomiting. With step-up dosing, these events were uncommon.
In the 240- to 300-mg daily step-up cohorts in phase 2, grade ≥3 nausea and diarrhea were observed in only 10% of patients each. Hematologic toxicities grade ≥3 were limited to anemia (11%) in the 240- to 300-mg daily cohort and neutropenia (10%) in the 150- to 180-mg daily cohort.
Treatment-emergent peripheral neuropathy was rare, occurring in only 6% of patients, with only 1 case of grade 3. Rash was reported in 7% of patients, with no grade ≥3. A total of 3 deaths were reported in the 5/14 dosing cohort before step-up dosing was instituted; 2 from upper gastrointestinal bleeding and 1 from disease progression.
“Our preliminary data suggest that step-up dosing is associated with improved tolerability, with fewer gastrointestinal adverse events observed, and less hematologic toxicity, although the numbers are small,” Dr Vij reported.
“With the phase 2 step-up dose of 150-180 mg daily, we have seen no grade 3 gastrointestinal toxicity. There’s also a hint that dose reductions and discontinuations for adverse events are less.”
Enrollment in the 2/7 and 5/14 schedules is continuing. The target enrollment for the phase 2 portion of the myeloma cohort is 94 patients. All current and newly enrolled patients are receiving extended-release tablets of oprozomib. Most patients receive premedication with antidiarrheal and antiemetic agents.—KS