title: Midostaurin does not prolong cardiac repolarization defined  in a thorough electrocardiogram trial in healthy volunteers.
abstract: OBJECTIVE
  Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin's effect on cardiac repolarization.
  
  
  METHODS
  This phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate-corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers.
  
  
  RESULTS
  The maximum mean QTc change from baseline corrected using Fridericia's correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported.
  
  
  CONCLUSIONS
  Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.
authors.affiliation: Novartis Oncology, East Hanover, NJ, USA. Adam.delCorral@novartis.com
authors.forename: Adam
authors.initials: A
authors.lastname: del Corral
authors.forename: Catherine
authors.initials: C
authors.lastname: Dutreix
authors.forename: Alice
authors.initials: A
authors.lastname: Huntsman-Labed
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lorenzo
authors.forename: Joel
authors.initials: J
authors.lastname: Morganroth
authors.forename: Robert
authors.initials: R
authors.lastname: Harrell
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001372:Aza Compounds / Q000009:adverse effects; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011804:Quinolines / Q000009:adverse effects; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D019311:Staurosporine; C059539:midostaurin; D000077266:Moxifloxacin