title: Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma.
abstract: Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN;
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: William I
authors.initials: WI
authors.lastname: Bensinger
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Todd M
authors.initials: TM
authors.lastname: Zimmerman
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ;
authors.forename: Craig B
authors.initials: CB
authors.lastname: Reeder
authors.affiliation: Institute for Myeloma and Bone Cancer Research, West Hollywood, CA;
authors.forename: James R
authors.initials: JR
authors.lastname: Berenson
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: Ai-Min
authors.initials: AM
authors.lastname: Hui
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: Jiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA;
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shou
authors.affiliation: Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY.
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001896:Boron Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015507:Drugs, Investigational / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; 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*; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D001896:Boron Compounds; D015507:Drugs, Investigational; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine