Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795).

3085 Background: The RAS/RAF/MEK and PI3K/AKT pathways are activated in many human cancers. GSK212 is a potent and selective allosteric inhibitor of MEK1/2 and GSK795 is a potent ATP-competitive inhibitor of all three isoforms of AKT. The objectives of this study were to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK212 dosed in combination with GSK795 in adults with advanced solid tumors. Methods: Both GSK212 and GSK795 are given orally, once daily. This is a three-part study: Part 1, dose escalation; Part 2, expansion in selected tumor types to evaluate recommended Phase II doses (RP2D); Part 3, PK/PD assessment using tumor biopsies or FDG-PET. Results: 23 patients (pts) received ≥1 dose of GSK212 and/or GSK795 with 7 remaining on study. Dose escalation has proceeded using a zone-based escalation procedure enabling evaluation of multiple combination doses in parallel cohorts: 0.5mg GSK212 + 25, 50 or 75mg GSK795, 1mg or 1.5mg GSK212 + 25mg GSK795, and 1mg GSK212 + 50mg GSK79...