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

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Abstract

Backgrounds

RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem MAPK signaling pathway inhibitor. The objectives of this phase I study were to determine MTD and to evaluate safety, PK, PD and anti-tumor activity in Japanese patients with advanced solid tumors.

Methods

72–144 hours after oral single dose administration of RO5126766 (0.8, 1.2, 1.8 and 2.25 mg/day), patients received oral RO5126766 administered on a continuous once daily dosing (QD) in 28-day cycles. The 3 + 3 dose-escalation design was used. PD was evaluated by pERK and pMEK inhibition in peripheral blood mononuclear cells (PBMCs).

Results

Twelve patients were enrolled in cohort of 0.8, 1.2, 1.8 and 2.25 mg/day. Considering that 2.25 mg/day had been defined as the MTD on the QD oral dosing regimen in another phase I study conducted in Europe, higher dose than 2.25 mg/day was not administered in this study. In the dose range tested, no DLT was observed and the MTD has not been defined. Main adverse events (AEs) included dermatitis acneiform, creatine phosphokinase (CPK) elevation and eye disorders. The plasma exposures of RO5126766 appeared to increase dose-linearly with long plasma half-life (t1/2) of 45.8–93.7 h. After multiple dose administration, steady-state conditions were reached by cycle 1 day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs were increased in a dose-dependent manner. Five of 12 patients achieved stable diseases including a case of melanoma with over 20% shrinkage.

Conclusions

RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced tumors.

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