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

• Published in: European journal of cancer (1990) Vol. 68; pp. 1 - 10
• Main Authors: Jamieson, David, Griffin, Melanie J, Sludden, Julieann, Drew, Yvette, Cresti, Nicola, Swales, Karen, Merriman, Mark, Allen, Rodger, Bevan, Paul, Buerkle, Markus, Mala, Carola, Coyle, Vicky, Rodgers, Lisa, Dean, Emma, Greystoke, Alastair, Banerji, Udai, Wilson, Richard H, Evans, T.R. Jeffery, Anthoney, Alan, Ranson, Malcolm, Boddy, Alan V, Plummer, Ruth
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2016
• Subjects: Abdominal Pain - chemically induced; Administration, Oral; Adult; Aged; Allosteric Regulation; Anorexia - chemically induced; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - metabolism; Chromatography, High Pressure Liquid; Chromatography, Liquid; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Diarrhea - chemically induced; Drug Eruptions - etiology; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Fatigue - chemically induced; Female; Glycogen Synthase Kinase 3 beta - drug effects; Glycogen Synthase Kinase 3 beta - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 2 - antagonists & inhibitors; Maximum Tolerated Dose; MEK inhibitor; Mesothelioma - drug therapy; Mesothelioma - metabolism; Middle Aged; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - drug effects; Mitogen-Activated Protein Kinase 3 - metabolism; Nausea - chemically induced; Neoplasms - drug therapy; Neoplasms - metabolism; Optimal biological dose; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pharmacodynamics; Pharmacokinetics; Phase I; Phosphoproteins - drug effects; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - drug effects; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Tandem Mass Spectrometry; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - metabolism; Pharmacodynamics; MEK inhibitor; Phase I; Optimal biological dose; Pharmacokinetics
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2016.08.026

Abstract 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.