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

Yi-Lin Chiu, Patricia Lorusso, Balakrishna Hosmane, Justin L Ricker, Walid Awni, Dawn M Carlson, Yi-Lin Chiu, Patricia Lorusso, Balakrishna Hosmane, Justin L Ricker, Walid Awni, Dawn M Carlson

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.

Trial registration: ClinicalTrials.gov NCT00733187.

Figures

Fig. 1
Fig. 1
Linifanib concentration versus QTcF change from baseline (ΔQTcF)

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Source: PubMed

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