A phase Ib dose-escalation study of GSK2256098 (FAKi) plus trametinib (MEKi) in patients with selected advanced solid tumors

2593 Background: The focal adhesion kinase (FAK) and MAPK pathways share common upstream activators and contribute to cell proliferation, differentiation, migration and survival. Dual inhibition of both pathways with GSK2256098 and trametinib, respectively, are synergistic in cellular growth and survival assays, especially in mesothelioma cell lines. Methods: This phase Ib study (NCT01938443, funded by GSK) evaluated GSK2256098 twice daily combined with trametinib once daily in pts with advanced solid malignancies enriching for mesothelioma. The objectives were to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 Nov 2014, 24 pts were enrolled (14 M, 10 F; median age 66 yr (range 30 to 78)). GSK2256098 at 250 or 500 mg twice-daily (BID) was orally co-administered with trametinib at 0.25, 0.375, 0.5 or 1 mg once-daily (QD) in 28-day cycles. Systemic exposure to trametinib was 2-4 X > than predicted for monotherapy causing DLTs (skin rash...