Purpose: In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation.Experimental Design: In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter.Results: The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve 0-24 , exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC 50 of 352 ng/ mL and maximum inhibition (E max ) of ∼91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy.Conclusions: The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials. Clin Cancer Res; 16(5); 1613-23. ©2010 AACR.The Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is a key signaling cascade involved in the regulation of cell cycle, proliferation, differentiation, and survival.Dysregulation of this pathway as a result of aberrant upstream growth factor receptor signaling (1), or by activating mutations in signaling molecules such as Ras and Raf themselves, has been implicated in tumor formation (2).MEK1/2 are central components of the Ras/Raf/MEK/ ERK pathway. They lie downstream of Ras and Raf and are attractive anticancer targets because inhibition of MEK1/2 can potentially block inappropriate signal transduction, originating from the cell surface or due to Ras/ Raf mutations (1-4).AZD6244 is a potent, selective, allosteric inhibitor of MEK1/2 that has shown activity in a number of cell-based growth assays and a variety of human tumor mouse xenograft models, including non-small cell lung cancer (NSCLC) and melanoma (5-7). The clinical efficacy of an oral free-base suspension of AZD6244 has been shown in a phase I trial in...

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