Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients

• Published in: Blood Vol. 124; no. 7; pp. 1038 - 1046
• Main Authors: Richardson, Paul G., Baz, Rachid, Wang, Michael, Jakubowiak, Andrzej J., Laubach, Jacob P., Harvey, R. Donald, Talpaz, Moshe, Berg, Deborah, Liu, Guohui, Yu, Jiang, Gupta, Neeraj, Di Bacco, Alessandra, Hui, Ai-Min, Lonial, Sagar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2014; American Society of Hematology
• Subjects: Administration, Oral; Aged; Aged, 80 and over; Area Under Curve; Boron Compounds - adverse effects; Boron Compounds - pharmacokinetics; Boron Compounds - therapeutic use; Clinical Trials and Observations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Exanthema - chemically induced; Fatigue - chemically induced; Female; Glycine - adverse effects; Glycine - analogs & derivatives; Glycine - pharmacokinetics; Glycine - therapeutic use; Humans; Male; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - pathology; Nausea - chemically induced; Neoplasm Recurrence, Local; Proteasome Inhibitors - adverse effects; Proteasome Inhibitors - pharmacokinetics; Proteasome Inhibitors - therapeutic use; Thrombocytopenia - chemically induced; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-01-548826

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/m2 (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m2. The maximum tolerated dose was 2.0 mg/m2, 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/m2). 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. •Twice-weekly oral ixazomib appears tolerable, with no severe neuropathy seen to date, in heavily pretreated multiple myeloma patients.•These phase 1 data suggest clinical activity including 76% stable disease or better, with durable responses and sustained disease control.