Phase i clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: Study NPI-0052-102 final results

Simon J. Harrison, Paul Mainwaring, Timothy Price, Michael J. Millward, Peeter Padrik, Craig R. Underhill, Paul K. Cannell, Steven D. Reich, Mohit Trikha, Andrew Spencer

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Abstract

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 I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 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 (0.075-0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II 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, and 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 (∼15-416 L) and clearance (∼0.9-22 L/minutes). Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic 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. Clin Cancer Res; 22(18); 4559-66.

Original languageEnglish
Pages (from-to)4559-4566
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
Publication statusPublished - 15 Sep 2016
Externally publishedYes

Cite this

Harrison, S. J., Mainwaring, P., Price, T., Millward, M. J., Padrik, P., Underhill, C. R., Cannell, P. K., Reich, S. D., Trikha, M., & Spencer, A. (2016). Phase i clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: Study NPI-0052-102 final results. Clinical Cancer Research, 22(18), 4559-4566. https://doi.org/10.1158/1078-0432.CCR-15-2616