A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors

Soria, J.C. et al. (2016) A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors. Annals of Oncology, 27(12), pp. 2268-2274. (doi: 10.1093/annonc/mdw427) (PMID:27733373)

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Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. Patients and methods: The dose of GSK2256098 was escalated in cohorts of patients with advanced cancer from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients and the PK determined. Paired tumor biopsies were obtained in select patients and the level of phospho-FAK (pFAK) determined. Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grade 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 hours. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ~80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n=14; 11.4 weeks merlin positive, n=9; 10.9 wks merlin status unknown, n=6). Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Brown, Dr Jennifer and Evans, Professor Jeff
Authors: Soria, J.C., Gan, H.K., Blagden, S.P., Plummer, R., Arkenau, H.T., Ranson, M., Evans, T.R.J., Zalcman, G., Bahleda, R., Hollebecque, A., Lemech, C., Dean, E., Brown, J., Gibson, D., Peddareddigari, V., Murray, S., Nebot, N., Mazumdar, J., Swartz, L., Auger, K.R., Fleming, R.A., Singh, R., and Millward, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Annals of Oncology
Publisher:Oxford University Press
ISSN (Online):1569-8041
Published Online:11 October 2016
Copyright Holders:Copyright © 2016 The Author
First Published:First published in Annals of Oncology 27(12): 2268-2274
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573449Experimental Cancer Medicine Centre (ECMC)Thomas EvansCancer Research UK (CAN-RES-UK)15584ICS - EXPERIMENTAL THERAPEUTICS