title: A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Drug Development Department at Gustave Roussy Cancer Campus, University Paris-Sud, Paris, France soria@igr.fr.
authors.forename: J C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.|School of Cancer Medicine, Latrobe University, Melbourne, Australia.
authors.forename: H K
authors.initials: HK
authors.lastname: Gan
authors.affiliation: Imperial College, Hammersmith Hospital, London.
authors.forename: S P
authors.initials: SP
authors.lastname: Blagden
authors.affiliation: Northern Centre for Cancer Care, Newcastle.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Sarah Cannon Research Institute, London.
authors.forename: H T
authors.initials: HT
authors.lastname: Arkenau
authors.affiliation: University of Manchester, Christie Hospital, Manchester.
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.affiliation: University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
authors.affiliation: Early Phases Clinical Trials Unit at Caen University Hospital, Caen, France.
authors.forename: G
authors.initials: G
authors.lastname: Zalcman
authors.affiliation: Drug Development Department at Gustave Roussy Cancer Campus, University Paris-Sud, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: Drug Development Department at Gustave Roussy Cancer Campus, University Paris-Sud, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Hollebecque
authors.affiliation: Sarah Cannon Research Institute, London.
authors.forename: C
authors.initials: C
authors.lastname: Lemech
authors.affiliation: University of Manchester, Christie Hospital, Manchester.
authors.forename: E
authors.initials: E
authors.lastname: Dean
authors.affiliation: University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gibson
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: V
authors.initials: V
authors.lastname: Peddareddigari
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: S
authors.initials: S
authors.lastname: Murray
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nebot
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mazumdar
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: L
authors.initials: L
authors.lastname: Swartz
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Auger
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Fleming
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Millward
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001706:Biopsy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000631:Aminopyridines; C000600809:GSK2256098; D006877:Hydroxamic Acids; D025581:Neurofibromin 2; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: NF2; focal adhesion kinase; merlin; mesothelioma; pharmacodynamics; phase I