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...

The aim of this prospective study was to evaluate the value of 18 F-FDG PET for the assessment of chemotherapy response in patients with non-small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18 F-FDG PET was performed before and at 5-8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MR Glu ]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MR Glu and SUV were calculated using Kaplan-Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of DMR Glu and DSUV, the difference in overall survival (P 5 0.017 for DMR Glu , P 5 0.018 for DSUV) and progressionfree survival (P 5 0.002 for DMR Glu , P 5 0.0009 for DSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for DSUV between response categories in progression-free survival (P 5 0.0003) as well as overall survival (P 5 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18 F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18 F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MR Glu ) in this patient population.