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|Ref Type||Journal Article|
|Authors||Honda K, Yamamoto N, Nokihara H, Tamura Y, Asahina H, Yamada Y, Suzuki S, Yamazaki N, Ogita Y, Tamura T|
|Title||Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors.|
|Journal||Cancer chemotherapy and pharmacology|
|Abstract Text||RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors.Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage 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).A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8-93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage.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 solid tumors.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||RO5126766||Phase I||Actionable||In a Phase I trial, RO5126766 demonstrated safety and some preliminary activity in Japanese patients with advanced solid tumors, with 42% (5/12) of patients achieving stable disease (PMID: 23860959).||23860959|