Phase Ib Dose-escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma
Mené sur 40 patients atteints d'un myélome multiple ayant récidivé ou progressé, cet essai de phase I évalue la dose maximale tolérée du carfilzomib, un inhibiteur sélectif du protéasome, en combinaison avec du lénalidomide et de la dexaméthasone à faible dose
Purpose: Carfilzomib, a selective proteasome inhibitor, has demonstrated safety and efficacy in relapsed and/or refractory multiple myeloma. This Phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a Phase II expansion study. Experimental Design: Patients with multiple myeloma who relapsed after 1-3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15-27 mg/m2 on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10-25 mg on Days 1-21; and dexamethasone 40 mg weekly. Results: Forty patients enrolled in 6 cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the Phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no Grade 3/4 neuropathy reported. Proteasome inhibition 1 hour post-dose was >80% in Cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and median duration of response and progression-free survival were 11.8 and 10.2 months, respectively. Conclusion: The maximum planned CRd dose-carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg-was recommended for further study, with promising safety and efficacy.