Results of a phase I, open-label, randomized, crossover study evaluating the effects of linifanib on QTc intervals in patients with solid tumors.

Abstract

PURPOSE:

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.

• Authors: Yi-Lin Chiu, Patricia Lorusso, Balakrishna Hosmane, Justin L Ricker, Walid Awni, Dawn M Carlson
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 73 Issue 1 Pg. 213-7 (Jan 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24241212 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• Phenylurea Compounds
• Protein Kinase Inhibitors
• linifanib
• Protein-Tyrosine Kinases

Topics

• Cross-Over Studies
• Electrocardiography (drug effects)
• Humans
• Indazoles (adverse effects)
• Neoplasms (drug therapy)
• Phenylurea Compounds (adverse effects)
• Protein Kinase Inhibitors (adverse effects)
• Protein-Tyrosine Kinases (antagonists & inhibitors)