475P - Final Analysis of Phase I and Pharmacokinetics/Pharmacodynamics (PK/PD) Study of RO5126766, A First-in-Class Dual Raf/Mek Inhibitor, in Japanese Patients With Advanced Solid Tumors

Abstract

ABSTRACT Background RO5126766 is a highly selective and orally active dual inhibitor of Raf and MEK, key enzymes in the MAPK signaling pathway. This was a phase I, dose-escalation study in Japanese patients with advanced solid tumors. This Phase I study was aimed to assess maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), safety evaluation, PK/PD analysis and exploratory analysis of anti-tumor activity. Methods Patients received an oral single dose administration of RO5126766 (0.8, 1.2, 1.8, and 2.25 mg) followed by continuous once daily dosing in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs). Archival tumor tissue or biopsy samples were collected to analyze the mutation status of K-Ras and B-Raf only from patients who had consented to provide samples. Results Twelve patients were enrolled into 4 sequential cohorts at 0.8, 1.2, 1.8, and 2.25 mg/day. As 2.25 mg/day had already been defined as the MTD of the QD oral dosing regimen in another phase I study conducted in Europe, doses higher than 2.25 mg/day were not administered. In the dose range tested, no DLTs were observed and the MTD was not defined. Frequent adverse events (AEs) included dermatitis acneiform, creatine phosphorkinase (CPK) elevation, and eye disorders. Plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t1/2) of 45.8 to 93.7 hours. Following multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8 (240 hours). No clear associations between PK parameters and occurrence of skin disorders, CPK elevation, or eye disorder were found. The inhibitory effects of RO5126766 on both pMEK and pERK in PBMCs increased in a dose-dependent manner. These inhibitory effects were achieved at >80% over the dose level of 1.2 mg at steady state phase. Five out of 12 patients achieved stable disease including a melanoma case with over 20 % shrinkage. Conclusions RO5126766 has a manageable safety profile up to 2.25 mg/day with a favorable PK/PD correlation in Japanese patients with advanced tumors. Disclosure K. Honda: 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. H. Nokihara: 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. H. Asahina: 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. S. Suzuki: 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. T. Tamura: This phase I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd.