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

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 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.

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.

Keywords: ECG; PARP inhibitor; Poly(ADP-ribose) polymerase; QT interval; Solid tumor; Veliparib.

Conflict of interest statement

W. Munasinghe, S. Stodtmann, D. Medina, D. Bergau, S. Nuthalapati, D. Hoffman, S. Shepherd, and H. Xiong: Employees and stakeholders of AbbVie and Abbott. A. Tolcher: Consulting or advisory role for AbbVie, Akebia, A.P. Pharma, ARIAD (inventive Health), ArQule, Asana, Astex Therapeutics, Baxalta, Bayer Healthcare, Bicycle, BIND Therapeutics, Blend Therapeutics, Boehringer-Ingelheim, Celator, Dicerna, Eli Lilly, Endocyte, Formation Biologics, Genmab, Heron, Idea Pharma, Ignyta, Janssen Research & Development LLC, Johnson & Johnson, Eli Lilly (Centralized Payment Services), LiquidNet, MedImmune, Mersana, Merus, Nanobiotix, OncoMed, Pharmacyclics, Pierre Fabre, Proximagen (PharmaWrite), Rigontec, Sanofi-Aventis, Symphogen, Upsher-Smith, Valent Technologies, Viventia, Zymeworks. E. Calvo, M. Jalving, and J. de Vos-Geelen: Declare that they have no conflicts of interest. M. Gordon: Research funding from AbbVie. Ethical approval All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Human and animal rights This article does not contain any studies with animals performed by any of the authors. Informed consent Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1

a QTcF and b baseline-adjusted QTcF (∆QTcF)a interval-time profiles. Data are means + standard deviations. c Baseline-adjusted drug-placebo difference in QTcF interval (∆∆QTcF). Data are point estimates plus 95 % upper-bound time profiles. aFour patients had missing baseline or all post-baseline ECG interval measurements and were not included in ∆QTcF analyses for the regimen in which the information was missing. ECG electrocardiogram, QTcF corrected QT interval using Fridericia’s formula

Fig. 2

Veliparib plasma concentration–time profile. Data are means + standard deviations; linear-log scale

Fig. 3

Exposure–response model. Veliparib plasma concentration-∆∆QTcF predictions; data represent median and upper 95 % confidence intervals. QTcF corrected QT interval using Fridericia’s formula, ∆∆QTcF baseline-adjusted drug-placebo difference in QTcF interval