507 - Phase I, open-label, randomized, crossover study evaluating the effects of linifanib on QTC intervals in patients with solid tumors

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Drug Development
Presenter Yi-Lin Chiu
Authors Y. Chiu1, P. Lorusso2, J. Ricker3, X. Li1, R. Pradhan1, D.M. Carlson4
  • 1Clinical Pharmacology And Pharmacometrics, Abbott, 60064 - Abbott Park/US
  • 2Eisenberg Center For Translational Therapeutics, Barbara Ann Karmanos Cancer Institute, 48201 - Detroit/US
  • 3Gprd, Abbott, 60064 - Abbott Park/US
  • 4Dept R48k, Abbott, 60064 - Abbott Park/US

Abstract

Background

Linifanib (ABT-869) is a novel, orally active and selective inhibitor of VEGF and PDGF family of receptor tyrosine kinases that has shown antitumor activity in multiple types of solid tumors. This study was conducted to evaluate the potential effects of linifanib on QTc prolongation in patients (pts) with advanced solid tumors.

Methods

Enrolled pts (N = 24; ≥18 years) had measurable disease refractory to standard therapies, ECOG PS 0-1, and adequate organ function. Pts received 2 sequences of regimens of 0.25 mg/kg orally administered linifanib up to a maximum dose of 17.5 mg. Pts received a morning dose on Days 1 and 7 under fasting and fed conditions in a crossover fashion. Serial triplicate ECG recordings were obtained on Day –1, and over 24 hours on Day 1 and 7; single recordings were obtained at screening and study completion or discontinuation. Plasma samples were collected for 72 hours on Day 1 and 7 for pharmacokinetic analysis. Effects of linifanib on cardiac repolarization were analyzed using a linear mixed effects model on time-matched baseline adjusted QTcF intervals. The primary end point was the time-matched difference for on-treatment QTcF from baseline (ΔQTcF). An intersection-union test was performed within the framework of the corresponding linear mixed effects model. The relationship between ΔQTcF and plasma linifanib concentration was explored using a linear mixed effects model.

Results

In the 24 pts evaluated, baseline QTcF ranged from 360.9 ms to 468.6 ms. After linifanib administration, the mean ΔQTcF ranged from –4.04 ms to 0.73 ms for the fasting regimen, and from –5.94 ms to –1.37 ms for the fed regimen. The upper 95% confidence bound was 4.30 ms (ie, <10 ms). The exposure-response analysis predicted a change in QTcF of 3.56 ms (P = 0.11) at a Cmax of 0.34 ug/mL with upper 95% confidence bound of 7.2 ms. No pt had QTcF >500 ms or change of >30 ms from baseline.

Conclusion

At the maximum tolerated dose of 0.25 mg/kg, linifanib had no effect on cardiac repolarization in pts with advanced solid tumors.

Disclosure

Y. Chiu: Full-time Abbott employee and stockholder.

P.M. LoRusso: Patricia LoRusso's institution receives research funding from Abbott.

J.L. Ricker: Full-time Abbott employee and stockholder.

X. Li: Full-time Abbott employee and stockholder.

R. Pradhan: Full-time Abbott employee and stockholder.

D.M. Carlson: Full-time Abbott employee and stockholder.