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 GSK795. Dose escalation is continuing. The RP2D for single-agent GSK212 is 2mg and the MTD for single agent GSK795 is 75mg. Dose-limiting toxicities (DLTs) are ≥14 day interruption of study drug for Grade 2 AST and ALT elevation and Grade 3 chest pain in association with sustained ventricular tachycardia. All DLTs were reversible with drug interruption. The most common adverse events (≥10%) were nausea (26%; G3/4 0%), AST elevation (22%; G3/4 9%), fatigue (22%; G3/4 0%), rash (22%; G3/4 0%), decreased appetite (17%; G3/4 0%), hypokalemia (17%; G3/4 0%), anemia (13%; G3/4 0%), confusional state (13%; G3/4 0%), dry mouth (13%; G3/4 0%), peripheral edema (13%; G3/4 0%), and vomiting (13%; G3/4 0%). At the lowest dose level (0.5mg/25mg) concentrations of each drug were similar when each compound was dosed alone or in combination. 3 of 13 pts evaluable for response had tumor regressions of 8% (ovarian), 16% (endometrial) and 17% (ovarian) after 8 weeks on study. Conclusions: The combination of the MEK1/2 inhibitor GSK212 and the AKT inhibitor GSK795 was well tolerated with reversible, predictable toxicities and has preliminary signals of clinical activity.