PMID- 29974203 OWN - NLM STAT- MEDLINE DCOM- 20190809 LR - 20240210 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 82 IP - 3 DP - 2018 Sep TI - An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer. PG - 457-468 LID - 10.1007/s00280-018-3632-6 [doi] AB - PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (DeltaQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for >/= 3 months. At steady state, the maximum DeltaQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide. FAU - Belderbos, Bodine P S I AU - Belderbos BPSI AD - Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. FAU - de Wit, Ronald AU - de Wit R AD - Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. r.dewit@erasmusmc.nl. FAU - Chien, Caly AU - Chien C AD - Janssen Research & Development, 1400 McKean Road, Spring House, PA, 19477, USA. FAU - Mitselos, Anna AU - Mitselos A AD - Janssen Research & Development BE, Turnhoutseweg 30, Beerse, Belgium. FAU - Hellemans, Peter AU - Hellemans P AD - Janssen Research & Development BE, Turnhoutseweg 30, Beerse, Belgium. FAU - Jiao, James AU - Jiao J AD - Janssen Research & Development, 920 Route 202 South, Raritan, NJ, 08869, USA. FAU - Yu, Margaret K AU - Yu MK AD - Janssen Research & Development, 10990 Wilshire Blvd., Suite 1200, Los Angeles, CA, 90024, USA. FAU - Attard, Gerhardt AU - Attard G AD - Research Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK. FAU - Bulat, Iurie AU - Bulat I AD - ARENSIA Exploratory Medicine's Research Unit, The Institute of Oncology, 30 N.Testemitanu str., 2025, Chisinau, Republic of Moldova. FAU - Edenfield, W Jeffrey AU - Edenfield WJ AD - GHS Cancer Institute, 900 West Faris Road, Greenville, SC, 29615, USA. FAU - Saad, Fred AU - Saad F AD - Centre Hospitalier de l'Universite de Montreal/CRCHUM, 900, rue St-Denis, porte R04-446, Montreal, Quebec, H2X 0A9, Canada. LA - eng GR - 22744/CRUK_/Cancer Research UK/United Kingdom PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20180705 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Androgen Receptor Antagonists) RN - 0 (Thiohydantoins) RN - 0 (apalutamide) MH - Aged MH - Aged, 80 and over MH - Androgen Receptor Antagonists/administration & dosage/adverse effects/pharmacokinetics MH - Electrocardiography, Ambulatory/*drug effects MH - Heart Rate/drug effects MH - Heart Ventricles/drug effects/physiopathology MH - Humans MH - Male MH - Middle Aged MH - Prostatic Neoplasms, Castration-Resistant/*drug therapy/metabolism/*physiopathology MH - Thiohydantoins/*administration & dosage/adverse effects/pharmacokinetics PMC - PMC6105166 OTO - NOTNLM OT - Apalutamide OT - Castration-resistant prostate cancer OT - Pharmacokinetics OT - QT interval OT - Ventricular repolarization COIS- CONFLICT OF INTEREST: Bodine Belderbos has held a consulting/advisory role and has received travel/accommodations/expenses from Astellas. Ronald de Wit has received advisory fees from Sanofi, Merck, Roche, and Lilly, and research grants from Erasmus MC Cancer Institute, Sanofi, and Bayer. Caly Chien is employed by Janssen Research & Development, LLC, and holds stock in Johnson & Johnson. Anna Mitselos is employed by Janssen Research & Development, LLC, and holds stock in Johnson & Johnson. Peter Hellemans is employed by Janssen Research & Development, LLC, and holds stock in Johnson & Johnson. James Jiao is employed by Janssen Research & Development, LLC, and holds stock in Johnson & Johnson. Margaret K. Yu is employed by Janssen Research & Development, LLC, and holds stock in Johnson & Johnson. Gerhardt Attard has received honoraria from Janssen and Astellas; has held a consulting or advisory role at Janssen, Astellas, Pfizer, Millennium Pharmaceuticals, Abbott Laboratories, Essa Pharmaceuticals, Bayer Pharmaceuticals, Veridex, Ventana, and Novartis; has served on speaker's bureau for Janssen, Astellas, Takeda, Sanofi-Aventis, and Ventana; has received research funding from Janssen, AstraZeneca, Arno Therapeutics, and Innocrin Pharma; holds patents, receives royalties, or has intellectual property with Institute of Cancer Research [ICR] rewards to inventors list of abiraterone acetate; has received travel, accommodations, and expenses from Janssen, Astellas, Pfizer, Ventana, Abbott Laboratories, Bayer Pharmaceuticals, and Essa Pharmaceuticals; and was employed by ICR through 8 Jan 2018. Iurie Bulat has nothing to disclose. Jeffrey W. Edenfield has nothing to disclose. Fred Saad has received grants, personal fees, and nonfinancial support from Janssen, Astellas, Sanofi, and Bayer. ETHICAL APPROVAL: All procedures performed in studies 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. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2018/07/06 06:00 MHDA- 2019/08/10 06:00 PMCR- 2018/07/05 CRDT- 2018/07/06 06:00 PHST- 2018/03/28 00:00 [received] PHST- 2018/06/22 00:00 [accepted] PHST- 2018/07/06 06:00 [pubmed] PHST- 2019/08/10 06:00 [medline] PHST- 2018/07/06 06:00 [entrez] PHST- 2018/07/05 00:00 [pmc-release] AID - 10.1007/s00280-018-3632-6 [pii] AID - 3632 [pii] AID - 10.1007/s00280-018-3632-6 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2018 Sep;82(3):457-468. doi: 10.1007/s00280-018-3632-6. Epub 2018 Jul 5.