PMID- 27709282 OWN - NLM STAT- MEDLINE DCOM- 20170526 LR - 20181113 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 78 IP - 5 DP - 2016 Nov TI - Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study. PG - 1003-1011 AB - 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. FAU - Munasinghe, Wijith AU - Munasinghe W AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. wijith.munasinghe@abbvie.com. FAU - Stodtmann, Sven AU - Stodtmann S AD - AbbVie Deutschland GmbH & Co KG, Ludwigshafen am Rhein, Germany. FAU - Tolcher, Anthony AU - Tolcher A AD - South Texas Accelerated Research Therapeutics, LLC, START, San Antonio, TX, United States. FAU - Calvo, Emiliano AU - Calvo E AD - South Texas Accelerated Research Therapeutics, LLC, START, START Madrid-Centro Integral Oncologico Clara Campal, Madrid, Spain. FAU - Gordon, Michael AU - Gordon M AD - Pinnacle Oncology Hematology, Scottsdale, AZ, United States. FAU - Jalving, Mathilde AU - Jalving M AD - University Medical Center Groningen, Groningen, The Netherlands. FAU - de Vos-Geelen, Judith AU - de Vos-Geelen J AD - Division of Medical Oncology, Department of Internal Medicine, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands. FAU - Medina, Diane AU - Medina D AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. FAU - Bergau, Dennis AU - Bergau D AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. FAU - Nuthalapati, Silpa AU - Nuthalapati S AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. FAU - Hoffman, David AU - Hoffman D AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. FAU - Shepherd, Stacie AU - Shepherd S AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. FAU - Xiong, Hao AU - Xiong H AD - AbbVie Inc., 1 N Waukegan Rd, North Chicago, IL, United States. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20161005 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Benzimidazoles) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 01O4K0631N (veliparib) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Algorithms MH - Benzimidazoles/*adverse effects/pharmacokinetics/therapeutic use MH - Cross-Over Studies MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Electrocardiography/drug effects MH - Endpoint Determination MH - Female MH - Heart Conduction System/drug effects MH - Humans MH - Long QT Syndrome/*chemically induced/physiopathology MH - Male MH - Middle Aged MH - Neoplasms/drug therapy MH - Poly(ADP-ribose) Polymerase Inhibitors/*adverse effects/pharmacokinetics/therapeutic use PMC - PMC5083757 OTO - NOTNLM OT - ECG OT - PARP inhibitor OT - Poly(ADP-ribose) polymerase OT - QT interval OT - Solid tumor OT - Veliparib COIS- 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. EDAT- 2016/10/28 06:00 MHDA- 2017/05/27 06:00 PMCR- 2016/10/05 CRDT- 2016/10/07 06:00 PHST- 2016/08/04 00:00 [received] PHST- 2016/09/06 00:00 [accepted] PHST- 2016/10/28 06:00 [pubmed] PHST- 2017/05/27 06:00 [medline] PHST- 2016/10/07 06:00 [entrez] PHST- 2016/10/05 00:00 [pmc-release] AID - 10.1007/s00280-016-3156-x [pii] AID - 3156 [pii] AID - 10.1007/s00280-016-3156-x [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2016 Nov;78(5):1003-1011. doi: 10.1007/s00280-016-3156-x. Epub 2016 Oct 5.