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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Abstract
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 |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 0923-7534 |
| 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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