PMID- 31260835 OWN - NLM STAT- MEDLINE DCOM- 20200716 LR - 20200716 IS - 1556-1380 (Electronic) IS - 1556-0864 (Linking) VI - 14 IP - 10 DP - 2019 Oct TI - Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC. PG - 1828-1838 LID - S1556-0864(19)30503-9 [pii] LID - 10.1016/j.jtho.2019.06.021 [doi] AB - INTRODUCTION: This first-time-in-humans study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed or refractory SCLC. METHODS: This phase I, multicenter, open-label study (NCT02034123) enrolled patients (>/=18 years old) with relapsed or refractory SCLC (after >/=1 platinum-containing chemotherapy or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary end point (Part 1) was to determine the safety, tolerability, and recommended dose and regimen of GSK2879552. Secondary end points were to characterize PK and PD parameters and measure disease control rate at week 16. Part 2 was not conducted. RESULTS: Between February 4, 2014, and April 18, 2017, a total of 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once daily and 3-mg or 4-mg intermittent dosing). In all, 22 patients completed the study; 7 withdrew, primarily owing to adverse events (AEs). Most patients (24 of 29 [83%]) had at least one treatment-related AE, most commonly thrombocytopenia (12 of 29 [41%]). Twelve serious AEs (SAEs) were reported by nine patients; six were considered treatment related, the most common of which was encephalopathy (four SAEs). Three patients died; one death was related to SAEs. PK was characterized by rapid absorption, slow elimination, and a dose-proportional increase in exposure. CONCLUSIONS: GSK2879552 is a potent, selective inhibitor of lysine demethylase 1A and has demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated, as the risk-benefit profile did not favor continuation. CI - Copyright (c) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Bauer, Todd M AU - Bauer TM AD - Sarah Cannon Research Institute, Nashville, Tennessee; Tennessee Oncology, PLLC, Nashville, Tennessee. FAU - Besse, Benjamin AU - Besse B AD - Gustave-Roussy Cancer Campus, Cancer Medicine Department, Villejuif, France; Paris-Sud University, Orday, France. FAU - Martinez-Marti, Alex AU - Martinez-Marti A AD - Vall d' Hebron Institute of Oncology and University Hospital, Barcelona, Spain. FAU - Trigo, Jose Manuel AU - Trigo JM AD - University Hospital Virgen de la Victoria, Malaga, Spain. FAU - Moreno, Victor AU - Moreno V AD - START Madrid-FJD, Jimenez Diaz Foundation Hospital, Madrid, Spain. FAU - Garrido, Pilar AU - Garrido P AD - Ramon y Cajal University Hospital, IRYCIS, Alcala University, Madrid, Spain. FAU - Ferron-Brady, Geraldine AU - Ferron-Brady G AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Wu, Yuehui AU - Wu Y AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Park, Jennifer AU - Park J AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Collingwood, Therese AU - Collingwood T AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Kruger, Ryan G AU - Kruger RG AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Mohammad, Helai P AU - Mohammad HP AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Ballas, Marc S AU - Ballas MS AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Dhar, Arindam AU - Dhar A AD - GlaxoSmithKline, Collegeville, Pennsylvania. FAU - Govindan, Ramaswamy AU - Govindan R AD - Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address: rgovindan@wustl.edu. LA - eng SI - ClinicalTrials.gov/NCT02034123 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20190628 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Benzoates) RN - 0 (Cyclopropanes) RN - 0 (GSK2879552) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Benzoates/pharmacokinetics/*therapeutic use MH - Cyclopropanes/pharmacokinetics/*therapeutic use MH - Dose-Response Relationship, Drug MH - Drug Resistance, Neoplasm/*drug effects MH - Female MH - Follow-Up Studies MH - Humans MH - Lung Neoplasms/*drug therapy/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Recurrence, Local/*drug therapy/pathology MH - Prognosis MH - *Salvage Therapy MH - Small Cell Lung Carcinoma/*drug therapy/pathology MH - Survival Rate MH - Tissue Distribution MH - Young Adult OTO - NOTNLM OT - GSK2879552 OT - Pharmacodynamics OT - Pharmacokinetics OT - Safety OT - Small cell lung carcinoma EDAT- 2019/07/02 06:00 MHDA- 2020/07/17 06:00 CRDT- 2019/07/02 06:00 PHST- 2019/02/06 00:00 [received] PHST- 2019/05/28 00:00 [revised] PHST- 2019/06/21 00:00 [accepted] PHST- 2019/07/02 06:00 [pubmed] PHST- 2020/07/17 06:00 [medline] PHST- 2019/07/02 06:00 [entrez] AID - S1556-0864(19)30503-9 [pii] AID - 10.1016/j.jtho.2019.06.021 [doi] PST - ppublish SO - J Thorac Oncol. 2019 Oct;14(10):1828-1838. doi: 10.1016/j.jtho.2019.06.021. Epub 2019 Jun 28.