Phase I (Ph) safety, pharmacodynamic (PD), and pharmacokinetic (PK) trial of a pure MEK inhibitor (i), RO4987655, in patients with advanced /metastatic solid tumor.

3017 Background: Mutations of Ras/Raf lead to a sustained and constitutive activation of ERK pathway. MEK1/2 is the only enzyme that activates ERK1/2; consequently MEK1/2 is a potential target to inhibit in cancers with an activated ERK pathway. RO4987655, a potent, highly selective ATP non-competitive MEK1i with an excellent selectivity profile, was tested in a 3+3 Ph1 study design. Objectives were determination of maximum tolerated dose (MTD), recommended Ph2 dose (RP2D), dose limiting toxicities (DLTs), safety/tolerability, PK/ PD and clinical activity. Methods: Patients (pts) with advanced/metastatic solid tumors received oral RO4987655 administered on a continuous daily dosing (QD) from 1-2.5 mg then twice daily (BID) from 3-21 mg total daily dose in 28 days (D) cycles. Blood PK samples were collected on cycle 1 (C1) [D 1, 8, 15 and 22]. Molecular target suppression was measured by pERKi in PBMC on C1 (D1, D15). Paired skin and tumor biopsies (optional) (baseline, C1D15) and sequential FDG-PET scans ...