Background: The Ras/Raf/MEK/ERK cascade is frequently activated in human cancers; MEK inhibition is an attractive therapeutic target for preventing tumor growth and angiogenesis. The investigational drug TAK-733 is a novel, orally available, selective, non-ATP competitive, allosteric inhibitor of MEK1/2. It has shown in-vivo antitumor activity against multiple human tumor xenograft models, particularly tumors with activating BRAF mutations or RAS mutations, mediated through induction of caspase-driven apoptosis. This study is the first clinical evaluation of TAK-733. Methods: The primary objectives of this phase I study are to evaluate the safety profile, characterize the pharmacokinetics (PK), and determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of oral TAK-733. Secondary objectives include evaluating the antitumor activity of TAK-733, including in melanoma pts with BRAF V600E mutation or wild-type. Exploratory objectives include the investigation of potential pharmacodynamic effects in peripheral blood (pERK), and assessment of any associations between antitumor activity and N/KRAS and BRAF mutations that may predict response to treatment. The study is composed of two stages. In the dose-escalation stage, approximately 30 pts with advanced nonhematologic malignancies will receive TAK-733 QD on days 1–21 of 28-day cycles from a starting dose of 0.2 mg; dose escalation will proceed via a single pt-cohort design (100% increments) and then a modified 3+3 design (40% increments) based on DLTs in cycle 1. Dosing of TAK-733 will then be investigated at or below the MTD, until the RP2D is determined. In the expansion stage, approximately 30 MEK/BRAF inhibitor-naïve pts with advanced unresectable melanoma, with either BRAF V600E or BRAF-wild type tumors, will be treated at the RP2D. For both stages, pts aged ≥18 years, with ECOG PS 0–2 and radiographically or clinically evaluable tumors are eligible. To date, 22 pts have been enrolled to the dose-escalation stage. This study is registered with ClinicalTrials.gov (NCT00948467).