title: A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma.
abstract: OBJECTIVE
  Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies.
  
  
  METHODS
  Carfilzomib (doses ranging from 1.2-27 mg/m(2)) was administered i.v. 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/m(2) during the first week (days 1, 2) and then escalated to 27 mg/m(2) thereafter.
  
  
  RESULTS
  A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m(2), there was evidence of activity among patients with multiple myeloma 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.
authors: H. Lee Moffitt Cancer and Research Center, Tampa, FL 33612, USA. melissa.alsina@moffitt.org
authors: Melissa
authors: M
authors: Alsina
authors: Suzanne
authors: S
authors: Trudel
authors: Richard R
authors: RR
authors: Furman
authors: Peter J
authors: PJ
authors: Rosen
authors: Owen A
authors: OA
authors: O'Connor
authors: Raymond L
authors: RL
authors: Comenzo
authors: Alvin
authors: A
authors: Wong
authors: Lori A
authors: LA
authors: Kunkel
authors: Christopher J
authors: CJ
authors: Molineaux
authors: Andre
authors: A
authors: Goy
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib