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

W. Munasinghe, S. Stodtmann, A. Tolcher, E. Calvo, M. Gordon, M. Jalving, Judith de Vos-Geelen, D. Medina, D. Bergau, S. Nuthalapati, D. Hoffman, S. Sepherd, H. Xiong

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Abstract

Purpose 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).
Methods 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 baselineadjusted 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.
Results Forty-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.
Conclusions 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
  • RADIATION-THERAPY
  • PHASE-I
  • COMBINATION
  • INHIBITORS
  • EFFICACY
  • PARP1

Cite this

Munasinghe, W., Stodtmann, S., Tolcher, A., Calvo, E., Gordon, M., Jalving, M., de Vos-Geelen, J., Medina, D., Bergau, D., Nuthalapati, S., Hoffman, D., Sepherd, S., & Xiong, H. (2016). Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study. Cancer Chemotherapy and Pharmacology, 78(5), 1003-1011. https://doi.org/10.1007/s00280-016-3156-x