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

Shaji K. Kumar, William I. Bensinger, Todd M. Zimmerman, Craig B. Reeder, James R. Berenson, Deborah Berg, Ai Min Hui, Neeraj Gupta, Alessandra Di Bacco, Jiang Yu, Yaping Shou, Ruben Niesvizky

Research output: Contribution to journalArticle

148 Scopus citations

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/m2. 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.

Original languageEnglish (US)
Pages (from-to)1047-1055
Number of pages9
JournalBlood
Volume124
Issue number7
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Kumar, S. K., Bensinger, W. I., Zimmerman, T. M., Reeder, C. B., Berenson, J. R., Berg, D., Hui, A. M., Gupta, N., Di Bacco, A., Yu, J., Shou, Y., & Niesvizky, R. (2014). Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood, 124(7), 1047-1055. https://doi.org/10.1182/blood-2014-01-548941