| Autor: |
Carla M.L. van Herpen, Paul D. Smith, Sarah M.A. George, Clive Morris, Mireille V. Cantarini, Kathryn H. Brown, Karl D. Lewis, S. Gail Eckhardt, Johanna N.H. Timmer-Bonte, Ingrid M.E. Desar, Stan B. Kaye, Debashis Sarker, Roshan Agarwal, Henk M.W. Verheul, D. Ross Camidge, Udai Banerji |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6518778 |
| Popis: |
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 curve0-24, 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 IC50 of 352 ng/mL and maximum inhibition (Emax) 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 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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