Author:

Keywords:

Delanzomib, CEP-18770, proteasome inhibitor, phase I, II study, relapsed, refractory multiple myeloma, Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, BORTEZOMIB, DEXAMETHASONE, CARFILZOMIB, LENALIDOMIDE, IXAZOMIB, AGENT, phase I/II study, relapsed/refractory multiple myeloma, Aged, Boronic Acids, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multiple Myeloma, Proteasome Inhibitors, Recurrence, Retreatment, Threonine, Treatment Outcome, 1103 Clinical Sciences, Immunology, 3201 Cardiovascular medicine and haematology

Abstract:

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (β5/β1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.