A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma
Mené sur 37 patients atteints d'un myélome multiple ou d'un lymphome réfractaire et/ou récidivant, cet essai de phase I évalue l'activité antitumorale et la toxicité du carfilzomib, un inhibiteur sélectif du protéasome
Purpose:Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma (MM). The objectives of this phase 1 study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. Experimental Design:Carfilzomib (doses ranging from 1.2-27 mg/m2) was administered intravenously on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n=37) was followed by a dose-expansion phase (n=11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m2 during the first week (Days 1, 2) and then escalated to 27 mg/m2 thereafter. Results:A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events (AEs) were manageable and primarily of Grade 1 or 2. The main hematologic AEs ≥ Grade 3 were anemia and thrombocytopenia. Notably, there were no observations of ≥ Grade 3 peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of <30 min but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15-27 mg/m2, there was evidence of activity among patients with MM and with non-Hodgkin lymphoma. Conclusions:Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE.