Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. Experimental Design: Phase 1 study (NPI-0052-102) evaluated the maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1 to 0.9 mg/m2 over 1-10 minutes on Days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075 to 0.6 mg/m2 over 1 minute to 2 hours on Days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended Phase 2 dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half life (<30 minutes), with high volume of distribution (~15 to 416 L) and clearance (~0.9 to 22 L/min). Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematological toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation.
- Received December 9, 2015.
- Revision received March 21, 2016.
- Accepted March 24, 2016.
- Copyright ©2016, American Association for Cancer Research.