TY - JOUR
T1 - Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC
AU - Bauer, Todd M.
AU - Besse, Benjamin
AU - Martinez-Marti, Alex
AU - Trigo, Jose Manuel
AU - Moreno, Victor
AU - Garrido, Pilar
AU - Ferron-Brady, Geraldine
AU - Wu, Yuehui
AU - Park, Jennifer
AU - Collingwood, Therese
AU - Kruger, Ryan G.
AU - Mohammad, Helai P.
AU - Ballas, Marc S.
AU - Dhar, Arindam
AU - Govindan, Ramaswamy
N1 - Funding Information:
This study (200858, NCT02034123 ) was funded by GlaxoSmithKline . The authors would like to thank Andre Acusta and Ahmed Khaled for their assistance with study analysis. Medical writing support in the form of developing drafts based on author input, editorial assistance, and submission of the final article was provided by Leigh O’Connor, PhD, and Clare Slater, PhD, CMPP, of Fishawack Indicia Ltd, United Kingdom, and was funded by GlaxoSmithKline . Dr. Dhar, Dr. Ferron-Brady, Dr. Park, Dr. Mohammad, Dr. Kruger, Dr. Govindan, and Dr. Wu contributed to the study conception or design. Dr. Bauer, Dr. Besse, Dr. Garrido, Dr. Trigo, Dr. Martinez-Marti, Dr. Moreno, and Dr. Kruger were involved in acquisition of data. Dr. Collingwood, Dr. Dhar, Dr. Ferron-Brady, and Dr. Ballas performed the data analysis or data interpretation. All authors contributed to the development of the article and approved the final version.
Funding Information:
Disclosure: Drs. Ballas, Collingwood, Dhar, Ferron-Brady, Kruger, Wu, and Mohammad are employees of, and hold stock and/or shares, in GlaxoSmithKline (GSK). Dr. Park was an employee of GSK at the time of the study and holds stock in GSK. Dr. Besse has received institutional grants for clinical and translational research from AbbVie, AMGEN, AstraZeneca, BIOGEN, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma. Dr. Martinez-Marti has provided consultation, attended advisory boards, and/or provided lectures for the following organizations: Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp and Dohme, Pfizer, Boehringer-Ingelheim. Dr. Bauer is an employee of Tennessee Oncology and Sarah Cannon Research Institute and has provided consultation or attended advisory boards for Guardant Health, Loxo, and Pfizer; in addition, he has received institutional funding from Daiichi Sankyo, Medpacto Inc., Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GSK, Novartis, Pfizer, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Roche, Aileron Therapeutics, BMS, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, and Foundation Medicine. Dr. Garrido has provided consulting and advisory services for Roche, MSD, BMS, Boehringer Ingelheim, Pfizer, AbbVie, Guardant Health, Novartis, Lilly, Astra-Zeneca, Jansen, Sysmex, Blueprint Medicines, and Takeda and has participated in speaking and public presentations for Roche, MSD, BMS, Pfizer, Novartis, and Boehringer Ingelheim; in addition, her institution has received direct research support to the project lead from Guardant Health, Sysmex, and Boehringer Ingelheim and financial support for clinical trials from Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, Celgene, Sanofi, GSK, and Theradex Oncology. Dr. Govindan has received honoraria for consulting from AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Merck, Nektar, Roche Genentech, and Pfizer; is a principal investigator or co-investigator on industry-sponsored clinical trials for which their institution receives funding and research support; and has work that is supported in part by a National Cancer Institute grant (1U01CA231844-01, Genomic and Functional Identification of Chemotherapy Resistance Mechanisms in Small Cell Lung Cancer). The remaining authors declare no conflict of interest.This study (200858, NCT02034123) was funded by GlaxoSmithKline. The authors would like to thank Andre Acusta and Ahmed Khaled for their assistance with study analysis. Medical writing support in the form of developing drafts based on author input, editorial assistance, and submission of the final article was provided by Leigh O'Connor, PhD, and Clare Slater, PhD, CMPP, of Fishawack Indicia Ltd, United Kingdom, and was funded by GlaxoSmithKline. Dr. Dhar, Dr. Ferron-Brady, Dr. Park, Dr. Mohammad, Dr. Kruger, Dr. Govindan, and Dr. Wu contributed to the study conception or design. Dr. Bauer, Dr. Besse, Dr. Garrido, Dr. Trigo, Dr. Martinez-Marti, Dr. Moreno, and Dr. Kruger were involved in acquisition of data. Dr. Collingwood, Dr. Dhar, Dr. Ferron-Brady, and Dr. Ballas performed the data analysis or data interpretation. All authors contributed to the development of the article and approved the final version.
Publisher Copyright:
© 2019 International Association for the Study of Lung Cancer
PY - 2019/10
Y1 - 2019/10
N2 - 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.
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.
KW - GSK2879552
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Safety
KW - Small cell lung carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85070059573&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2019.06.021
DO - 10.1016/j.jtho.2019.06.021
M3 - Article
C2 - 31260835
AN - SCOPUS:85070059573
SN - 1556-0864
VL - 14
SP - 1828
EP - 1838
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 10
ER -