title: Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.
abstract: Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾ 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾ 3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾ 3 events were reported. Plasma exposure increased dose proportionally from 0.5-3.11 mg/m(2); terminal half-life was 4-12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾ 32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.
authors.affiliation: Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Assouline
authors.affiliation: Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chang
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Cheson
authors.affiliation: Rocky Mountain Cancer Center, Denver, CO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rifkin
authors.affiliation: Tower Cancer Research Foundation, Beverly Hills, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hamburg
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: R
authors.initials: R
authors.lastname: Reyes
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: A-M
authors.initials: AM
authors.lastname: Hui
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Di Bacco
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shou
authors.affiliation: Weill Cornell Medical College, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D001896:Boron Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000453:epidemiology; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000453:epidemiology; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine