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

被引：175

作者：

Banerji, Udai ^{[1
]}

Camidge, D. Ross ^{[2
]}

Verheul, Henk M. W. ^{[3
]}

Agarwal, Roshan

Sarker, Debashis

Kaye, Stan B.

Desar, Ingrid M. E. ^{[4
]}

Timmer-Bonte, Johanna N. H. ^{[4
]}

Eckhardt, S. Gail ^{[2
]}

Lewis, Karl D. ^{[2
]}

Brown, Kathryn H. ^{[5
]}

Cantarini, Mireille V. ^{[5
]}

Morris, Clive ^{[5
]}

George, Sarah M. A. ^{[5
]}

Smith, Paul D. ^{[5
]}

van Herpen, Carla M. L. ^{[4
]}

机构：

[1] Royal Marsden Hosp, Inst Canc Res, Drug Dev Unit, Sutton SM2 5PT, Surrey, England

[2] Univ Colorado, Ctr Canc, Aurora, CO USA

[3] Univ Med Ctr, Utrecht, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Med Oncol, NL-6525 ED Nijmegen, Netherlands

[5] AstraZeneca, Macclesfield, Cheshire, England

来源：

CLINICAL CANCER RESEARCH | 2010年 / 16卷 / 05期

关键词：

KINASE; CI-1040; PATHWAY; GROWTH; POTENT; COLON;

D O I：

10.1158/1078-0432.CCR-09-2483

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1613 / 1623

页数：11

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