Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16477
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dc.contributor.authorSoria, Jean-Charles-
dc.contributor.authorGan, Hui K-
dc.contributor.authorBlagden, SP-
dc.contributor.authorPlummer, R-
dc.contributor.authorArkenau, HT-
dc.contributor.authorRanson, M-
dc.contributor.authorEvans, TR-
dc.contributor.authorZalcman, G-
dc.contributor.authorBahleda, R-
dc.contributor.authorHollebecque, A-
dc.contributor.authorLemech, C-
dc.contributor.authorDean, E-
dc.contributor.authorBrown, J-
dc.contributor.authorGibson, D-
dc.contributor.authorPeddareddigari, V-
dc.contributor.authorMurray, S-
dc.contributor.authorNebot, N-
dc.contributor.authorMazumdar, J-
dc.contributor.authorSwartz, L-
dc.contributor.authorAuger, KR-
dc.contributor.authorFleming, RA-
dc.contributor.authorSingh, R-
dc.contributor.authorMillward, M-
dc.date2016-10-11-
dc.date.accessioned2017-01-03T21:52:46Z-
dc.date.available2017-01-03T21:52:46Z-
dc.date.issued2016-12-
dc.identifier.citationAnnals of Oncology 2016; 27(12): 2268-2274en_US
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/16477-
dc.description.abstractBACKGROUND: 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.en_US
dc.subjectNF2en_US
dc.subjectFocal adhesion kinaseen_US
dc.subjectMerlinen_US
dc.subjectMesotheliomaen_US
dc.subjectPharmacodynamicsen_US
dc.subjectPhase Ien_US
dc.titleA phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumorsen_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleAnnals of Oncologyen_US
dc.identifier.affiliationDrug Development Department at Gustave Roussy Cancer Campus, University Paris-Sud, Paris, Franceen_US
dc.identifier.affiliationOlivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Victoria, Australiaen_US
dc.identifier.affiliationSchool of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australiaen_US
dc.identifier.affiliationImperial College, Hammersmith Hospital, London, UKen_US
dc.identifier.affiliationNorthern Centre for Cancer Care, Newcastle, UKen_US
dc.identifier.affiliationSarah Cannon Research Institute, London, UKen_US
dc.identifier.affiliationUniversity of Manchester, Christie Hospital, Manchester, UKen_US
dc.identifier.affiliationUniversity of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UKen_US
dc.identifier.affiliationEarly Phases Clinical Trials Unit at Caen University Hospital, Caen, Franceen_US
dc.identifier.affiliationGlaxoSmithKline, Research Triangle Park, NC, USAen_US
dc.identifier.affiliationGlaxoSmithKline Upper Providence, Collegeville, PA, USAen_US
dc.identifier.affiliationSchool of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australiaen_US
dc.identifier.pubmedurihttps://pubmed.ncbi.nlm.nih.gov/27733373en_US
dc.identifier.doi10.1093/annonc/mdw427en_US
dc.type.contentTexten_US
dc.type.austinJournal Articleen_US
local.name.researcherGan, Hui K
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.openairetypeJournal Article-
crisitem.author.deptMedical Oncology-
crisitem.author.deptOlivia Newton-John Cancer Wellness and Research Centre-
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