Phase I Marizomib Results Support Investigation For Hard-To-Treat Multiple Myeloma

Early marizomib results point to possible role in the treatment of relapsed and/or refractory multiple myeloma

medwireNews: Phase I dose-escalation study findings suggest the irreversible Proteasome inhibitor marizomib may be a feasible treatment of patients with multiple myeloma unresponsive to current therapies.

Marizomib was given at a schedule A dose of 0.1–0.9 mg/m2 for up to 10 minutes on days 1, 8 and 15 of a 4-week cycle to 42 patients with solid tumours, lymphoma or leukaemia. A second schedule B group of 44 patients, the majority (n=35) of whom had relapsing and/or remitting multiple myeloma (RRMM), were given marizomib 0.075–0. 6 mg/m2 for between 1 minute and 2 hours on days 1, 4, 8 and 11 of a 3-week cycle. 

Patients with RRMM were also given dexamethasone, say Simon Harrison, from Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, and co-investigators.

In all, 95.2% of schedule A patients and 88.6% of schedule B patients had at least one treatment-emergent adverse event, most commonly fatigue and nausea, with treatment discontinued in 10% and 5% of patients, respectively. There were no grade 4 adverse events and dose-limiting toxicities included gait disturbance, intermittent aphasia and visual hallucinations, the researchers say.

The schedule A marizomib dose suitable for phase II trial was set at 0.7 mg/m2 infusion over 10 minutes, while the schedule B alternative schedule was 0.5 mg/m2 over 2 hours.

Of the patients who received schedule A dosing, one patient with transformed marginal zone lymphoma experienced a complete response that lasted 10 cycles of treatment, and 29% of those with solid tumours and one patient with leukaemia had stable disease for a short duration.

Twenty-seven patients with RRMM were assessed for response to schedule B treatment, of whom 14.8% achieved an objective response, including four partial responses lasting a median of 27 weeks. There were four minimal responses and 12 patients with stable disease.

There were 10 RRMM patients who received the recommended phase II trial dose for schedule B and these individuals had a median progression-free survival of 20.4 weeks.

“The compound has activity in relapsed and refractory multiple myeloma with a good safety profile and a noncross-reactive toxicity profile compared with the current standard-of-care agents such as thalidomide, lenalidomide, bortezomib, carfilzomib, and ixazomib”, the study authors say.

“The findings in this clinical trial and preclinical studies form the rationale for further exploring marizomib (NPI-0052) in a recommended phase II dose study in combination with pomalidomide and dexamethasone in patients with refractory multiple myeloma, which remains an area of unmet clinical need”, they write in Clinical Cancer Research.

Reference

Harrison SJ, Mainwaring P, Price T, et al. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: Study NPI-0052-102 final results. Clin Cancer Res 2016; Advance online publication 29 July. DOI:10.1158/1078-0432.CCR-15-2616

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