A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.
MetadataShow full item record
<h4>Purpose</h4>We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.<h4>Experimental design</h4>Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.<h4>Results</h4>Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.<h4>Conclusions</h4>WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.
Version of record
Carcinoma, Non-Small-Cell Lung
Bile Duct Neoplasms
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Ribosomal Protein S6 Kinases, 70-kDa
Protein Kinase Inhibitors
Chromatography, High Pressure Liquid
Maximum Tolerated Dose
Uterine Cervical Neoplasms
Proto-Oncogene Proteins c-akt
Tandem Mass Spectrometry
Glycogen Synthase Kinase 3 beta
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
License start date
European journal of cancer (Oxford, England : 1990), 2016, 68 pp. 1 - 10
Showing items related by title, author, creator and subject.
Aarts, M; Sharpe, R; Garcia-Murillas, I; Gevensleben, H; Hurd, MS; Shumway, SD; Toniatti, C; Ashworth, A; Turner, NC (2012-06)Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. ...
Wan, PTC; Garnett, MJ; Roe, SM; Lee, S; Niculescu-Duvaz, D; Good, VM; Jones, CM; Marshall, CJ; Springer, CJ; Barford, D; Marais, R; Cancer Genome Project (2004-03)Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase ...
Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors. Whittaker, SR; Cowley, GS; Wagner, S; Luo, F; Root, DE; Garraway, LA (2015-12)RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a ...