title: A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors.
abstract: BACKGROUND
  Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors.
  
  
  METHODS
  In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m(2); Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability.
  
  
  RESULTS
  Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported.
  
  
  CONCLUSIONS
  Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.
authors.affiliation: Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042 Rennes Cedex, France. t.lesimple@rennes.unicancer.fr
authors.forename: Thierry
authors.initials: T
authors.lastname: Lesimple
authors.forename: Julien
authors.initials: J
authors.lastname: Edeline
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carrothers
authors.forename: Frédérique
authors.initials: F
authors.lastname: Cvitkovic
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.forename: Hervé
authors.initials: H
authors.lastname: Léna
authors.forename: Nicolas
authors.initials: N
authors.lastname: Penel
authors.forename: Geoff J
authors.initials: GJ
authors.lastname: Edwards
authors.forename: Kenneth
authors.initials: K
authors.lastname: Law
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Allan
authors.initials: A
authors.lastname: Kristensen
authors.forename: Larisa
authors.initials: L
authors.lastname: Reyderman
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D016001:Confidence Intervals; D003710:Demography; D004562:Electrocardiography; D005260:Female; D005663:Furans / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006339:Heart Rate; D006801:Humans; D007659:Ketones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000503:physiopathology; D014463:Ultrasonography; D000095662:Polyether Polyketides
chemical_list: D005663:Furans; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides