Results of a phase I, open-label, randomized, crossover study evaluating the effects of linifanib on QTc intervals in patients with solid tumors.
OBJECTIVE
Linifanib is a selective inhibitor of the vascular endothelial growth factor and platelet-derived growth factor family of tyrosine kinase inhibitors. The purpose of this high-precision QT study was to evaluate the effects of linifanib on cardiac repolarization in patients with advanced metastatic tumors.


METHODS
Enrolled patients (n = 24) had measurable disease refractory to standard therapies, ECOG performance status of 0-1, and adequate organ function. Patients were randomized in a 2-sequence, 2-period crossover design. Serial ECG measurements and pharmacokinetic samples were collected for each crossover period. An intersection-union test was performed for time-matched baseline-adjusted QTcF intervals. An exposure-response analysis was explored to correlate the plasma concentration and QTcF.


RESULTS
The maximum 95 % upper confidence bound for the baseline-adjusted QTcF was 4.3 ms at hour 3 at the maximum tolerated linifanib dose of 0.25 mg/kg. Linifanib did not meet the regulatory threshold (10 ms) for QT prolongation. Exposure-response modeling showed that the QTcF change was not significant at the maximum plasma concentration.


CONCLUSIONS
Linifanib does not significantly affect cardiac repolarization in patients with advanced solid tumors.
AbbVie, Inc., North Chicago, IL, USA, yi-lin.chiu@abbvie.com.
Yi-Lin
YL
Chiu
Patricia
P
Lorusso
Balakrishna
B
Hosmane
Justin L
JL
Ricker
Walid
W
Awni
Dawn M
DM
Carlson
D018592:Cross-Over Studies; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D007191:Indazoles / Q000009:adverse effects*; D009369:Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C513486:linifanib; D011505:Protein-Tyrosine Kinases