title: A Phase I cardiac safety and pharmacokinetic study of tivozanib hydrochloride in patients with advanced solid tumors.
abstract: Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib's effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.5 mg of tivozanib orally, once daily, for 21 days. Safety evaluations, serial blood samples for pharmacokinetic measurements, and time-matched, triplicate, 12-lead electrocardiograms (ECG) were collected. Fifty patients were evaluable. The maximum change in QTcF was 9.3 milliseconds (90% confidence interval [CI] 5-13.6), occurring 2.5 hours after dosing on Day 21. The central tendency change across all time points was +2.2 milliseconds. The slope of the exposure-ΔQTcF relationship was 0.08464 ms/ng/mL, with a predicted QTcF change of 8.27 milliseconds at the average tivozanib Tmax of 118.1 ng/mL (upper CI 12.6 milliseconds). There were no QTcF values >500 milliseconds or significant changes from baseline observed in heart rate, PR interval, and QRS complex. These data, evaluated along with other tivozanib preclinical and clinical study results, suggest that administration of 1.5 mg tivozanib for 21 days has a minimal effect on cardiac repolarization or ECG morphology in oncology subjects.
authors.affiliation: Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Moore
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Monette M
authors.initials: MM
authors.lastname: Cotreau
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Wilson
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Strahs
authors.affiliation: AVEO Oncology, Cambridge, MA, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Vargo
authors.affiliation: Virginia G. Piper Cancer Center and TGen, Scottsdale, AZ, USA.
authors.forename: Manpreet
authors.initials: M
authors.lastname: Chadha
mesh_terms: D000200:Action Potentials; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology; D066126:Cardiotoxicity; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C553176:tivozanib
keywords: QTc; cardiac; pharmacokinetic; solid tumor; tivozanib