PMID- 27733373
OWN - NLM
STAT- MEDLINE
DCOM- 20171226
LR  - 20240210
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Linking)
VI  - 27
IP  - 12
DP  - 2016 Dec
TI  - A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal 
      adhesion kinase inhibitor, in patients with advanced solid tumors.
PG  - 2268-2274
LID - 10.1093/annonc/mdw427 [doi]
AB  - 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  approximately 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.
CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the European 
      Society for Medical Oncology. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Soria, J C
AU  - Soria JC
AD  - Drug Development Department at Gustave Roussy Cancer Campus, University 
      Paris-Sud, Paris, France soria@igr.fr.
FAU - Gan, H K
AU  - Gan HK
AD  - Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, 
      Australia.
AD  - School of Cancer Medicine, Latrobe University, Melbourne, Australia.
FAU - Blagden, S P
AU  - Blagden SP
AD  - Imperial College, Hammersmith Hospital, London.
FAU - Plummer, R
AU  - Plummer R
AD  - Northern Centre for Cancer Care, Newcastle.
FAU - Arkenau, H T
AU  - Arkenau HT
AD  - Sarah Cannon Research Institute, London.
FAU - Ranson, M
AU  - Ranson M
AD  - University of Manchester, Christie Hospital, Manchester.
FAU - Evans, T R J
AU  - Evans TR
AD  - University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
FAU - Zalcman, G
AU  - Zalcman G
AD  - Early Phases Clinical Trials Unit at Caen University Hospital, Caen, France.
FAU - Bahleda, R
AU  - Bahleda R
AD  - Drug Development Department at Gustave Roussy Cancer Campus, University 
      Paris-Sud, Paris, France.
FAU - Hollebecque, A
AU  - Hollebecque A
AD  - Drug Development Department at Gustave Roussy Cancer Campus, University 
      Paris-Sud, Paris, France.
FAU - Lemech, C
AU  - Lemech C
AD  - Sarah Cannon Research Institute, London.
FAU - Dean, E
AU  - Dean E
AD  - University of Manchester, Christie Hospital, Manchester.
FAU - Brown, J
AU  - Brown J
AD  - University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.
FAU - Gibson, D
AU  - Gibson D
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Peddareddigari, V
AU  - Peddareddigari V
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Murray, S
AU  - Murray S
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Nebot, N
AU  - Nebot N
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Mazumdar, J
AU  - Mazumdar J
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Swartz, L
AU  - Swartz L
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Auger, K R
AU  - Auger KR
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Fleming, R A
AU  - Fleming RA
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Singh, R
AU  - Singh R
AD  - GlaxoSmithKline, Research Triangle Park, NC and Upper Providence, Collegeville, 
      USA.
FAU - Millward, M
AU  - Millward M
AD  - School of Medicine and Pharmacology, University of Western Australia, Sir Charles 
      Gairdner Hospital, Perth, Australia.
LA  - eng
GR  - 12946/CRUK_/Cancer Research UK/United Kingdom
GR  - DH_/Department of Health/United Kingdom
GR  - 20409/CRUK_/Cancer Research UK/United Kingdom
GR  - 11650/CRUK_/Cancer Research UK/United Kingdom
GR  - CSO_/Chief Scientist Office/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161011
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Aminopyridines)
RN  - 0 (GSK2256098)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Neurofibromin 2)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Aminopyridines/*administration & dosage/adverse effects/pharmacokinetics
MH  - Biopsy
MH  - Disease-Free Survival
MH  - Dose-Response Relationship, Drug
MH  - Drug-Related Side Effects and Adverse Reactions/classification/pathology
MH  - Female
MH  - Focal Adhesion Protein-Tyrosine Kinases/*antagonists & inhibitors/genetics
MH  - Humans
MH  - Hydroxamic Acids/*administration & dosage/adverse effects/pharmacokinetics
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/blood/*drug therapy/genetics/pathology
MH  - Neurofibromin 2/genetics
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/pharmacokinetics
OTO - NOTNLM
OT  - NF2
OT  - focal adhesion kinase
OT  - merlin
OT  - mesothelioma
OT  - pharmacodynamics
OT  - phase I
EDAT- 2016/10/14 06:00
MHDA- 2017/12/27 06:00
CRDT- 2016/10/14 06:00
PHST- 2016/07/01 00:00 [received]
PHST- 2016/08/30 00:00 [revised]
PHST- 2016/08/31 00:00 [accepted]
PHST- 2016/10/14 06:00 [pubmed]
PHST- 2017/12/27 06:00 [medline]
PHST- 2016/10/14 06:00 [entrez]
AID - S0923-7534(19)36550-0 [pii]
AID - 10.1093/annonc/mdw427 [doi]
PST - ppublish
SO  - Ann Oncol. 2016 Dec;27(12):2268-2274. doi: 10.1093/annonc/mdw427. Epub 2016 Oct 
      11.