title: A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.
abstract: OBJECTIVE
  To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors.
  
  
  METHODS
  A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done.
  
  
  RESULTS
  Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group.
  
  
  CONCLUSIONS
  Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation.
authors.affiliation: Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Rossella
authors.initials: R
authors.lastname: Bertulli
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Philippe
authors.initials: P
authors.lastname: Cassier
authors.forename: Monica
authors.initials: M
authors.lastname: Davey
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
authors.forename: Daniel
authors.initials: D
authors.lastname: Pink
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Wing
authors.initials: W
authors.lastname: Cheung
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Bailey
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Veronese
authors.forename: Annette
authors.initials: A
authors.lastname: Reichardt
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib