• Kyriakos P Papadopoulos, David S Siegel, David H Vesole, Peter Lee, Steven T Rosen, Naseem Zojwalla, Joseph R Holahan, Susan Lee, Zhengping Wang, and Ashraf Badros.
• Kyriakos P. Papadopoulos and Joseph R. Holahan, South Texas Accelerated Research Therapeutics, San Antonio, TX; David S. Siegel and David H. Vesole, John Theurer Cancer Center, Hackensack, NJ; Peter Lee, Tower Cancer Research Foundation, Beverly Hills; Naseem Zojwalla, Susan Lee, and Zhengping Wang, Onyx Pharmaceuticals, South San Francisco, CA; Steven T. Rosen, Northwestern Medical Center, Chicago, IL; and Ashraf Badros, Greenebaum Cancer Center, University of Maryland, Baltimore, MD. kyri.papadopoulos@start.stoh.com.
• J. Clin. Oncol. 2015 Mar 1;33(7):732-9.

PurposeCarfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.Patients And MethodsPatients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m(2), followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m(2). Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk).ResultsThirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m(2) were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m(2). Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m(2) cohort). Increasing carfilzomib dosing from 20 to 56 mg/m(2) resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m(2) of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib.ConclusionCarfilzomib administered as a 30-minute IV infusion at 56 mg/m(2) (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.© 2014 by American Society of Clinical Oncology.

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