title: Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients.
abstract: Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
authors.forename: Rachid
authors.initials: R
authors.lastname: Baz
authors.affiliation: The University of Texas MD. Anderson Cancer Center, Houston, TX;
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA; and.
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Berg
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Liu
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Bacco
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA; and.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001896:Boron Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine