Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16477
Title: A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors
Austin Authors: Soria, Jean-Charles;Gan, Hui K ;Blagden, SP;Plummer, R;Arkenau, HT;Ranson, M;Evans, TR;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, KR;Fleming, RA;Singh, R;Millward, M
Affiliation: Drug Development Department at Gustave Roussy Cancer Campus, University Paris-Sud, Paris, France
Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Imperial College, Hammersmith Hospital, London, UK
Northern Centre for Cancer Care, Newcastle, UK
Sarah Cannon Research Institute, London, UK
University of Manchester, Christie Hospital, Manchester, UK
University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK
Early Phases Clinical Trials Unit at Caen University Hospital, Caen, France
GlaxoSmithKline, Research Triangle Park, NC, USA
GlaxoSmithKline Upper Providence, Collegeville, PA, USA
School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
Issue Date: Dec-2016
metadata.dc.date: 2016-10-11
Publication information: Annals of Oncology 2016; 27(12): 2268-2274
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 was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was 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 grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. 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%, and -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 weeks 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16477
DOI: 10.1093/annonc/mdw427
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/27733373
Type: Journal Article
Subjects: NF2
Focal adhesion kinase
Merlin
Mesothelioma
Pharmacodynamics
Phase I
Appears in Collections:Journal articles

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