ATNT-06: EVALUATION OF THE SAFETY OF GSK2256098 AND PHARMACOKINETICS OF ¹¹C-GSK2256098 IN PATIENTS WITH RECURRENT GLIOBLASTOMA BY POSITRON EMISSION TOMOGRAPHY (PET) IMAGING

BACKGROUND: Focal adhesion kinase (FAK) is overexpressed in glioblastoma (GBM) and is associated with poor prognosis. The FAK inhibitor GSK2256098 inhibits growth, migration, and invasion and induces apoptosis in a subset of GBM cell lines. Pharmacokinetic (PK) studies in mice and rats with an intact blood brain barrier indicate that the penetration of GSK2256098 into the CNS is poor. The purpose of this study was to determine the safety, systemic PK, and distribution of GSK2256098 into the brain and tumor tissue in patients (pts) with GBM (NCT01138033). METHODS: Pts with recurrent GBM received 750-1000mg of GSK2256098 orally, twice daily until disease progression or withdrawal due to adverse events (AEs). Serial PK samples were collected in blood on Days 1 and 15. On a single day between Days 9-20, pts received a microdose (≤10 µg) of ¹¹C-GSK2256098 (≤ 500MBq) by IV administration and scanned by PET over 90 minutes. Pts were assessed for safety throughout the study and disease assessment scans were performed every six weeks. RESULTS: As of the March 15, 2015 data cutoff, 10 pts were enrolled (7 males, 3 females; median age 48.5 y, range 33-65 y) and 4 and 6 pts received 750 mg and 1000 mg BID of GSK2256098 respectively. AEs (≥25%) regardless of causality were fatigue (50%), diarrhea (40%), vomiting (40%), headache (30%), and somnolence (30%). Based on radioactivity data obtained during PET in 4 pts (3 at 1000mg, 1 at 750mg BID), GSK2256098 is estimated to achieve normal brain and tumor concentrations of 30-55% and 75-170% respectively of blood concentrations at equilibrium. No structural radiologic responses have been seen to date. One pt remains on study for 6 months. CONCLUSIONS: GSK2256098 achieves concentrations in tumor exceeding those associated with preclinical activity. Evaluation of lower doses of GSK2256098 is ongoing.