Phase I and pharmacokinetics/pharmacodynamics (PK/PD) study of MEK inhibitor, RO4987655, in Japanese patients with advanced solid tumors.

Abstract

116 Background: RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the MAPK signaling pathway. This was a phase I, non-randomized, open-label, dose-escalation study in Japanese patients (pts) with advanced solid tumors. Primary objectives were determination of maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), safety evaluation and PK analysis. Secondary objectives were PD analysis and exploratory analysis of RO4987655’s anti-tumor activity according to the RECIST 1.0 criteria. Methods: Patients received an oral single dose of RO4987655 (1, 2, 4, 5, and 6.5 mg) (Cycle 0) followed by continuous once daily dosing (QD, 1, 2, and 4 mg/day) then twice daily dosing (4, 5, and 6.5 mg BID, total daily dose: 8, 10 and 13 mg/day) in 28-day cycles. A 3 + 3 dose-escalation design was used. Blood samples for PK analysis were collected in Cycle 0 (Day 1, 2 and 3) and in Cycle 1 (Day 1, 8, 15 and 22). PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs) using FACS analysis. Results: In dose-escalation, 25 pts were enrolled. After the MTD was defined, 6 pts were added to the MTD dose for further confirmation of safety profile. Tumor types included esophageal (n=8), colorectal (n=8) and non-small cell lung cancer (NSCLC) (n=4). MTD was defined as 8 mg/day due to 4 DLTs of Grade 3 creatine phosphokinase (CPK) elevation. Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders, particularly macular edema and visual impairment. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 hours. After multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. An esophageal cancer pt confirmed partial response with over 50% shrinkage and 6 pts including NSCLC noted as stable disease ≥16 weeks by independent assessment. Conclusions: RO4987655 is tolerable with a favorable PK/PD correlation in Japanese pts with advanced solid tumors. Exploratory analysis of biomarker is ongoing. Clinical trial information: JapicCTI-111490.