PMID- 29788497
OWN - NLM
STAT- MEDLINE
DCOM- 20191018
LR  - 20200930
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 20
IP  - 12
DP  - 2018 Nov 12
TI  - A study of the focal adhesion kinase inhibitor GSK2256098 in patients with 
      recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098.
PG  - 1634-1642
LID - 10.1093/neuonc/noy078 [doi]
AB  - BACKGROUND: GSK2256098 is a novel oral focal adhesion kinase (FAK) inhibitor. 
      Preclinical studies demonstrate growth inhibition in glioblastoma cell lines. 
      However, rodent studies indicate limited blood-brain barrier (BBB) penetration. 
      In this expansion cohort within a phase I study, the safety, tolerability, 
      pharmacokinetics (PK), and clinical activity of GSK2256098 were evaluated in 
      patients with recurrent glioblastoma. Biodistribution and kinetics of 
      [11C]GSK2256098 were assessed in a substudy using positron-emission tomography 
      (PET). METHODS: Patients were treated with GSK2256098 until disease progression 
      or withdrawal due to adverse events (AEs). Serial PK samples were collected on 
      day 1. On a single day between days 9 and 20, patients received a microdose of 
      intravenous [11C]GSK2256098 and were scanned with PET over 90 minutes with 
      parallel PK sample collection. Response was assessed by MRI every 6 weeks. 
      RESULTS: Thirteen patients were treated in 3 dose cohorts (1000 mg, 750 mg, 500 
      mg; all dosed twice daily). The maximum tolerated dose was 1000 mg twice daily. 
      Dose-limiting toxicities were related to cerebral edema. Treatment-related AEs 
      (>25%) were diarrhea, fatigue, and nausea. Eight patients participated in the PET 
      substudy, with [11C]GSK2256098 VT (volume of distribution) estimates of 0.9 in 
      tumor tissue, 0.5 in surrounding T2 enhancing areas, and 0.4 in normal brain. 
      Best response of stable disease was observed in 3 patients, including 1 patient 
      on treatment for 11.3 months. CONCLUSIONS: GSK2256098 was tolerable in patients 
      with relapsed glioblastoma. GSK2256098 crossed the BBB at low levels into normal 
      brain, but at markedly higher levels into tumor, consistent with tumor-associated 
      BBB disruption. Additional clinical trials of GSK2256098 are ongoing.
FAU - Brown, Nicholas F
AU  - Brown NF
AD  - NIHR UCLH Clinical Research Facility, University College London Hospitals NHS 
      Foundation Trust, London, UK.
AD  - Department of Oncology, UCL Cancer Institute, London, UK.
FAU - Williams, Matthew
AU  - Williams M
AD  - Computational Oncology Lab, Institute of Global Health Innovation, South 
      Kensington Campus, Imperial College, London, UK.
AD  - Radiotherapy Department, Charing Cross Hospital, London, UK.
FAU - Arkenau, Hendrik-Tobias
AU  - Arkenau HT
AD  - Department of Oncology, UCL Cancer Institute, London, UK.
AD  - Sarah Cannon Research Institute UK, London, UK.
FAU - Fleming, Ronald A
AU  - Fleming RA
AD  - GlaxoSmithKline, Research Triangle Park, Durham, North Carolina, USA.
FAU - Tolson, Jerry
AU  - Tolson J
AD  - GlaxoSmithKline, Research Triangle Park, Durham, North Carolina, USA.
FAU - Yan, Li
AU  - Yan L
FAU - Zhang, Jianping
AU  - Zhang J
AD  - PAREXEL International, Durham, North Carolina, USA.
FAU - Singh, Rajendra
AU  - Singh R
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Auger, Kurt R
AU  - Auger KR
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Lenox, Laurie
AU  - Lenox L
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
FAU - Cox, David
AU  - Cox D
AD  - GlaxoSmithKline Research & Development Ltd, Uxbridge, UK.
FAU - Lewis, Yvonne
AU  - Lewis Y
AD  - GlaxoSmithKline, Collegeville, Pennsylvania, USA.
AD  - Imanova Ltd, Centre for Imaging Sciences, London, UK.
FAU - Plisson, Christophe
AU  - Plisson C
AD  - Imanova Ltd, Centre for Imaging Sciences, London, UK.
FAU - Searle, Graham
AU  - Searle G
AD  - Imanova Ltd, Centre for Imaging Sciences, London, UK.
FAU - Saleem, Azeem
AU  - Saleem A
AD  - Imanova Ltd, Centre for Imaging Sciences, London, UK.
FAU - Blagden, Sarah
AU  - Blagden S
AD  - NIHR/Wellcome Trust Imperial CRF, Imperial Centre for Translational and 
      Experimental Medicine, Hammersmith Hospital, London, UK.
FAU - Mulholland, Paul
AU  - Mulholland P
AD  - NIHR UCLH Clinical Research Facility, University College London Hospitals NHS 
      Foundation Trust, London, UK.
AD  - Department of Oncology, UCL Cancer Institute, London, UK.
LA  - eng
SI  - ClinicalTrials.gov/NCT01138033
GR  - Wellcome Trust/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Aminopyridines)
RN  - 0 (Carbon Radioisotopes)
RN  - 0 (GSK2256098)
RN  - 0 (Hydroxamic Acids)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
SB  - IM
EIN - Neuro Oncol. 2020 Jun 9;22(6):894. Swartz, Lisa [removed]. PMID: 32506127
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aminopyridines/pharmacokinetics/*therapeutic use
MH  - Carbon Radioisotopes/*pharmacokinetics
MH  - Cohort Studies
MH  - Female
MH  - Focal Adhesion Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Follow-Up Studies
MH  - Glioblastoma/*drug therapy/pathology
MH  - Humans
MH  - Hydroxamic Acids/pharmacokinetics/*therapeutic use
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy/pathology
MH  - Prognosis
MH  - Tissue Distribution
MH  - Young Adult
PMC - PMC6231205
EDAT- 2018/05/23 06:00
MHDA- 2019/10/19 06:00
PMCR- 2019/11/12
CRDT- 2018/05/23 06:00
PHST- 2018/05/23 06:00 [pubmed]
PHST- 2019/10/19 06:00 [medline]
PHST- 2018/05/23 06:00 [entrez]
PHST- 2019/11/12 00:00 [pmc-release]
AID - 4998845 [pii]
AID - noy078 [pii]
AID - 10.1093/neuonc/noy078 [doi]
PST - ppublish
SO  - Neuro Oncol. 2018 Nov 12;20(12):1634-1642. doi: 10.1093/neuonc/noy078.