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

Jamieson, D. et al. (2016) 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. European Journal of Cancer, 68, pp. 1-10. (doi: 10.1016/j.ejca.2016.08.026) (PMID:27693888)

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Purpose: 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. Experimental design: 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. Results: 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. Conclusions: 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Evans, Professor Jeff and Rodgers, Dr Lisa and Wilson, Professor Richard
Authors: Jamieson, D., Griffin, M. J., Sludden, J., Drew, Y., Cresti, N., Swales, K., Merriman, M., Allen, R., Bevan, P., Buerkle, M., Mala, C., Coyle, V., Rodgers, L., Dean, E., Greystoke, A., Banerji, U., Wilson, R. H., Evans, T.R. J., Anthoney, A., Ranson, M., Boddy, A. V., and Plummer, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:European Journal of Cancer
ISSN (Online):1879-0852
Published Online:28 September 2016
Copyright Holders:Copyright © 2016 Elsevier Ltd.
First Published:First published in European Journal of Cancer 68(1):1-10
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573443Experimental Cancer Medicine Centre (ECMC)Thomas EvansCancer Research UK (CAN-RES-UK)15584ICS - EXPERIMENTAL THERAPEUTICS