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: Paul G Richardson, Rachid Baz, Michael Wang, Andrzej J Jakubowiak, Jacob P Laubach, R Donald Harvey, Moshe Talpaz, Deborah Berg, Guohui Liu, Jiang Yu, Neeraj Gupta, Alessandra Di Bacco, Ai-Min Hui, Sagar Lonial
• Journal: Blood (Blood) Vol. 124 Issue 7 Pg. 1038-46 (Aug 14 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24920586 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• Boron Compounds
• Proteasome Inhibitors
• ixazomib
• Glycine

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Area Under Curve
• Boron Compounds (adverse effects, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Exanthema (chemically induced)
• Fatigue (chemically induced)
• Female
• Glycine (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Male
• Middle Aged
• Multiple Myeloma (drug therapy, pathology)
• Nausea (chemically induced)
• Neoplasm Recurrence, Local
• Proteasome Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Thrombocytopenia (chemically induced)
• Treatment Outcome