A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098

Neuro Oncol. 2018 Nov 12;20(12):1634-1642. doi: 10.1093/neuonc/noy078.


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.

Trial registration: ClinicalTrials.gov NCT01138033.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / therapeutic use*
  • Carbon Radioisotopes / pharmacokinetics*
  • Cohort Studies
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Follow-Up Studies
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / therapeutic use*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Tissue Distribution
  • Young Adult


  • Aminopyridines
  • Carbon Radioisotopes
  • GSK2256098
  • Hydroxamic Acids
  • Focal Adhesion Protein-Tyrosine Kinases

Associated data

  • ClinicalTrials.gov/NCT01138033