title: A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma.
abstract: BACKGROUND
  Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study.
  
  
  METHODS
  The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase.
  
  
  RESULTS
  With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2(duration of response, 5.2 to ≥21.2 months).
  
  
  CONCLUSIONS
  The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. ajai.chari@mssm.edu.
authors.forename: Ajai
authors.initials: A
authors.lastname: Chari
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Myo
authors.initials: M
authors.lastname: Htut
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Zonder
authors.affiliation: Baylor Research Institute, Dallas, Texas.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fay
authors.affiliation: University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.affiliation: Multiple Myeloma Research Consortium, Norwalk, Connecticut.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Levy
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lau
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Burt
authors.affiliation: Array BioPharma Inc, Boulder, Colorado.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Tunquist
authors.affiliation: Array BioPharma Inc, Boulder, Colorado.
authors.forename: Brandi W
authors.initials: BW
authors.lastname: Hilder
authors.affiliation: Array BioPharma Inc, Boulder, Colorado.
authors.forename: Selena A
authors.initials: SA
authors.lastname: Rush
authors.affiliation: Array BioPharma Inc, Boulder, Colorado.
authors.forename: Duncan H
authors.initials: DH
authors.lastname: Walker
authors.affiliation: Array BioPharma Inc, Boulder, Colorado.
authors.forename: Mieke
authors.initials: M
authors.lastname: Ptaszynski
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069286:Bortezomib / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016879:Salvage Therapy; D013830:Thiadiazoles / Q000008:administration & dosage
chemical_list: D000069286:Bortezomib; D003907:Dexamethasone; D013830:Thiadiazoles; C544550:filanesib
keywords: bortezomib; dexamethasone; filanesib; multiple myeloma; neoplasm recurrence; proteasome inhibitors; recurrent/refractory