title: Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma.
abstract: OBJECTIVE
  Carfilzomib 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.
  
  
  METHODS
  Patients 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).
  
  
  RESULTS
  Thirty-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.
  
  
  CONCLUSIONS
  Carfilzomib 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.
authors.affiliation: 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.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Siegel
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Vesole
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.affiliation: 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.
authors.forename: Naseem
authors.initials: N
authors.lastname: Zojwalla
authors.affiliation: 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.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Holahan
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Badros
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004417:Dyspnea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007673:Kidney Cortex Necrosis / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009325:Nausea / Q000139:chemically induced; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011507:Proteinuria / Q000139:chemically induced; D012008:Recurrence; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D003907:Dexamethasone