title: Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study.
abstract: OBJECTIVE
  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.
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. wijith.munasinghe@abbvie.com.
authors.forename: Wijith
authors.initials: W
authors.lastname: Munasinghe
authors.affiliation: AbbVie Deutschland GmbH & Co KG, Ludwigshafen am Rhein, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Stodtmann
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, START, San Antonio, TX, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.affiliation: South Texas Accelerated Research Therapeutics, LLC, START, START Madrid-Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, AZ, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Jalving
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos-Geelen
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Medina
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bergau
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: Silpa
authors.initials: S
authors.lastname: Nuthalapati
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hoffman
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: Stacie
authors.initials: S
authors.lastname: Shepherd
authors.affiliation: AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001562:Benzimidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D023381:Endpoint Determination; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib
keywords: ECG; PARP inhibitor; Poly(ADP-ribose) polymerase; QT interval; Solid tumor; Veliparib