title: An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma.
abstract: An open-label single-arm multicenter pilot phase II study of the next-generation selective proteasome inhibitor carfilzomib was conducted in 46 patients with relapsed and refractory multiple myeloma (MM) after ≥ 2 previous therapies. The best overall response rate (ORR) was 16.7%, with a median duration of response of 7.2 months. This pilot study was the first phase II single-agent trial conducted with carfilzomib.
  
  
  BACKGROUND
  Carfilzomib is a next-generation selective proteasome inhibitor that irreversibly binds its target and has demonstrated single-agent activity in patients with bortezomib-resistant multiple myeloma (MM). PX-171-003-A0, an open-label single-arm multicenter pilot phase II study, enrolled 46 patients with relapsed MM after ≥ 2 previous therapies including bortezomib and an immunomodulator (thalidomide or lenalidomide) and disease refractory to the last treatment regimen preceding study entry.
  
  
  METHODS
  Patients received carfilzomib 20 mg/m(2) intravenously on days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles. Responses in 42 evaluable patients were assessed per International Myeloma Working Group Uniform Response Criteria, with minimal response assessed per European Group for Blood and Marrow Transplantation (EBMT) criteria.
  
  
  RESULTS
  The primary endpoint of best ORR was 16.7%, including 7 partial responses. Median duration of response was 7.2 months. Clinical benefit response (CBR) rate was 23.8% with a median duration of response of 13.8 months. The most common treatment-emergent adverse events (AEs) of any grade were anemia (73.9%), fatigue (69.6%), and thrombocytopenia (50.0%). Notably, peripheral neuropathy and neuropathy-related AEs were generally mild and infrequent.
  
  
  CONCLUSIONS
  This pilot study was the first phase II single-agent trial conducted with carfilzomib. Based on these findings, the study was amended to test a higher carfilzomib dose in an additional 250 patients (PX-171-003-A1).
authors.affiliation: Mount Sinai Medical Center, New York, NY 10029, USA. sundar.jagannath@mssm.edu
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Nizar
authors.initials: N
authors.lastname: Bahlis
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.forename: Lori A
authors.initials: LA
authors.lastname: Kunkel
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: David S
authors.initials: DS
authors.lastname: Siegel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011719:Pyrazines / Q000494:pharmacology; D055502:Secondary Prevention
chemical_list: D001897:Boronic Acids; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; C524865:carfilzomib