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

Abstract 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.