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Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma.

TitlePhase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma.
Publication TypeJournal Article
Year of Publication2014
AuthorsKumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui A-M, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R
JournalBlood
Volume124
Issue7
Pagination1047-55
Date Published2014 Aug 14
ISSN1528-0020
KeywordsAdministration, Oral, Adult, Aged, Area Under Curve, Boron Compounds, Diarrhea, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Resistance, Neoplasm, Drugs, Investigational, Fatigue, Female, Glycine, Humans, Male, Middle Aged, Multiple Myeloma, Nausea, Neoplasm Recurrence, Local, Proteasome Inhibitors, Remission Induction, Thrombocytopenia, Treatment Outcome, Vomiting
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.

DOI10.1182/blood-2014-01-548941
Alternate JournalBlood
PubMed ID24904120
PubMed Central IDPMC4468583
Grant ListP30 CA015083 / CA / NCI NIH HHS / United States