Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study

Wijith Munasinghe*, Sven Stodtmann, Anthony Tolcher, Emiliano Calvo, Michael Gordon, Mathilde Jalving, Judith de Vos-Geelen, Diane Medina, Dennis Bergau, Silpa Nuthalapati, David Hoffman, Stacie Shepherd, Hao Xiong

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
209 Downloads (Pure)

Abstract

Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-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).

Eligible 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 (a dagger a dagger 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 a dagger a dagger QTcF was <10 ms for all time points. An exposure-response analysis was also performed.

Forty-seven patients were enrolled. Maximum mean a dagger a dagger QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean a dagger a dagger 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.

Single-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.

Original languageEnglish
Pages (from-to)1003-1011
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume78
Issue number5
DOIs
Publication statusPublished - Nov-2016

Keywords

  • Veliparib
  • Poly(ADP-ribose) polymerase
  • PARP inhibitor
  • QT interval
  • ECG
  • Solid tumor
  • PARP INHIBITORS
  • RADIATION-THERAPY
  • CANCER-THERAPY
  • THOROUGH QT
  • PHASE-I
  • COMBINATION
  • EFFICACY

Cite this