3037 Background: BAY 43–9006 (BAY) is a novel signaling inhibitor that acts through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. BAY inhibits CRAF and BRAF (wild type/V599E mutant) and inhibits growth of melanoma xenografts. In vitro data indicate that BAY inhibits CYP2C19, CYP2D6 and CYP3A4 with Ki values of 17 μM, 22 μM, and 29 μM, respectively. This phase I/II study was initiated to evaluate the effect of BAY on specific substrates of these enzymes, investigate alterations in tumor perfusion and vascular permeability using dynamic contrast-enhanced (DCE) MRI, and the effect of BAY on kinase activity and gene expression. Methods: BAY was given from day 1 to 28 of a 28-day cycle at 400 mg bid. PK data were collected on Day 28 of the first cycle. Omeprazole, midazolam, and dextromethorphan were administered on day -1 of cycle 1 and day 28 of cycle 1 for evaluation of the effect of BAY administration on known CYP metabolic pathways. Tumor samples were obtained pretreatment for BRAF mutation analysis. DCE-MRI and biopsies of accessible lesions were performed at baseline and after 4 weeks. Response was assessed every 2 cycles using RECIST criteria. Patients (pts) with disease progression on BAY alone could initiate carboplatin/paclitaxel and continue BAY until subsequent progression. Results: 22 melanoma pts (median age 58, PS 0–1) were enrolled. 15 pts received ≥ 1 prior systemic therapy, and 68% had AJCC M1c disease. As in previous studies, BAY was well-tolerated at this dose and schedule. Grade 2/3 toxicities in the first cycle included: hand-foot syndrome (2/0), hypertension (1/0), and pruritus (1/0). There were one PR and 12 SD as best response in 12 patients. Median time to progression was 4 months (range 0–9+). PK, BRAF mutation analysis, MAP kinase pathway activity, and DCE-MRI data are being analyzed. Conclusions: BAY 43–9006 is well-tolerated as a single agent and results in disease stabilization in a subset of patients with melanoma. The relationship of this effect to PK, BRAF mutation status, MAP kinase activity and alterations in tumor blood flow, and the effect of sorafenib on probe substrates of CYP2C19, CYP2D6 and CYP3A4 will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer Bayer Bayer