451P - Phase I and Pharmacokinetics/Pharmacodynamics (PK/PD) Study of Mek Inhibitor, RO4987655, in Japanese Patients with Advanced Solid Tumors

Abstract

ABSTRACT Background RO4987655, an oral and selective inhibitor of MEK, is a key enzyme of the MAPK signaling pathway. This was a phase I, non-randomized, open-label, dose-escalation study in Japanese patients 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). Results As of March 2012, 25 patients were enrolled in 6 cohorts of 1, 2, 4, 8, 10, and 13 mg/day. Four DLTs were observed in the 13 mg/day (n = 2) and 10 mg/day (n = 2) cohorts, all of them reversible Grade 3 creatine phosphokinase (CPK) elevation. MTD was defined as 8 mg/day. Most commonly related adverse events (AEs) included dermatitis acneiform, CPK elevation, and eye disorders. Plasma exposure of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life (t1/2) of 14.0 to 24.4 hours. After multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8 (240 hours). The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. Conclusions The MTD of RO4987655 for Japanese patients was defined as 8 mg/day. RO4987655 has a manageable safety profile with a favorable PK/PD correlation in Japanese patients with advanced solid tumors. Disclosure S. Nakamichi: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. K. Honda: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. H. Wakui: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd.