title: Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1.
abstract: Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: schedule A (0.025-0.7 mg/m(2) once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m(2) twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and the RP2D was established as 0.7 mg/m(2) infused over 10 minutes. Schedule B was administered to 36 patients, and the RP2D was determined to be 0.5 mg/m(2) infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: School of Medicine, University of Chicago, Chicago, IL;
authors.forename: Todd M
authors.initials: TM
authors.lastname: Zimmerman
authors.affiliation: The Ohio State University, Columbus, OH;
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.affiliation: The University of Michigan, Ann Arbor, MI;
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY;
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA; and.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: School of Medicine, University of Chicago, Chicago, IL;
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.affiliation: Triphase Accelerator, San Diego, CA.
authors.forename: Steven
authors.initials: S
authors.lastname: Reich
authors.affiliation: Triphase Accelerator, San Diego, CA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Trikha
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D007783:Lactones; D011758:Pyrroles; D013792:Thalidomide; C475865:marizomib; D003907:Dexamethasone; C467566:pomalidomide