Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results.
OBJECTIVE
Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors.


METHODS
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/m(2) 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/m(2) 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/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) 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. ©2016 AACR.
The Peter MacCallum Cancer Centre, East Melbourne and Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia. Simon.Harrison@petermac.org.
Simon J
SJ
Harrison
Mater Adult Hospital South Brisbane, Australia (currently Icon Cancer Care, South Brisbane, Australia).
Paul
P
Mainwaring
Queen Elizabeth Hospital, Adelaide, Australia.
Timothy
T
Price
Sir Charles Gairdner Hospital, Nedlands, Western Australia. University of Western Australia, Perth, Australia.
Michael J
MJ
Millward
Tartu University Hospital, Tartu, Estonia.
Peeter
P
Padrik
Border Medical Oncology, Wodonga, Australia.
Craig R
CR
Underhill
Royal Perth Hospital, Perth Australia, Australia.
Paul K
PK
Cannell
Triphase Accelerator, San Diego, California.
Steven D
SD
Reich
Triphase Accelerator, San Diego, California.
Mohit
M
Trikha
The Alfred Hospital, Melbourne, Australia.
Andrew
A
Spencer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; C475865:marizomib