The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer

Udai Banerji, D. Ross Camidge, Henk M. W. Verheul, Roshan Agarwal, Debashis Sarker, Stan B. Kaye, Ingrid M. E. Desar, Johanna N. H. Timmer-Bonte, S. Gail Eckhardt, Karl D. Lewis, Kathryn H. Brown, Mireille V. Cantarini, Clive Morris, Sarah M. A. George, Paul D. Smith, Carla M. L. van Herpen

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184 Citations (Scopus)

Abstract

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-tetrade-canoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC50 of 352 ng/mL and maximum inhibition (E-max) of similar to 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. (C) 2010 AACR.
Original languageEnglish
Pages (from-to)1613 - 1623
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number5
DOIs
Publication statusPublished - 1 Mar 2010

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