Effect of veliparib ABT-888 on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover studyReportar como inadecuado




Effect of veliparib ABT-888 on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Cancer Chemotherapy and Pharmacology

, Volume 78, Issue 5, pp 1003–1011

First Online: 05 October 2016Received: 04 August 2016Accepted: 06 September 2016DOI: 10.1007-s00280-016-3156-x

Cite this article as: Munasinghe, W., Stodtmann, S., Tolcher, A. et al. Cancer Chemother Pharmacol 2016 78: 1003. doi:10.1007-s00280-016-3156-x

Abstract

PurposeVeliparib ABT-888 is an orally bioavailable potent inhibitor of polyADP-ribose polymerase PARP-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia’s formula QTcF.

MethodsEligible patients with advanced solid tumors received single-dose oral veliparib 200 mg or 400 mg or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo ∆∆QTcF at six post-dose time points. Absence of clinically relevant QTcF effect was shown if the 95 % upper confidence bound UCB for the mean ∆∆QTcF was <10 ms for all time points. An exposure–response analysis was also performed.

ResultsForty-seven patients were enrolled. Maximum mean ∆∆QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean ∆∆QTcF was 3.6 ms, with a 95 % UCB of 6.1 ms. No patient had a QTcF value >480 ms or change from baseline in QTcF interval >30 ms. Treatment-emergent adverse events TEAEs were experienced by 36.2, 48.9, and 47.8 % of patients while receiving veliparib 200 mg, veliparib 400 mg, and placebo, respectively. Most common TEAEs were nausea 12.8 % and myalgia 8.5 % after veliparib 200 mg, nausea 8.5 % and vomiting 8.5 % after veliparib 400 mg, and nausea 6.5 % after placebo.

ConclusionsSingle-dose veliparib 200 mg or 400 mg did not result in clinically significant QTc prolongation and was well tolerated in patients with advanced solid tumors.

KeywordsVeliparib PolyADP-ribose polymerase PARP inhibitor QT interval ECG Solid tumor  Download fulltext PDF



Autor: Wijith Munasinghe - Sven Stodtmann - Anthony Tolcher - Emiliano Calvo - Michael Gordon - Mathilde Jalving - Judith de Vos-

Fuente: https://link.springer.com/



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