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.

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Publication Date
2016-11Author
Jamieson, D
Griffin, MJ
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, RH
Evans, TRJ
Anthoney, A
Ranson, M
Boddy, AV
Plummer, R
Type
Journal Article
Metadata
Show full item recordAbstract
<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.
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Subject
Humans
Neoplasms
Mesothelioma
Cholangiocarcinoma
Carcinoma, Non-Small-Cell Lung
Bile Duct Neoplasms
Esophageal Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Lung Neoplasms
Drug Eruptions
Fatigue
Abdominal Pain
Anorexia
Diarrhea
Nausea
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Ribosomal Protein S6 Kinases, 70-kDa
Phosphoproteins
Protein Kinase Inhibitors
Chromatography, Liquid
Chromatography, High Pressure Liquid
Administration, Oral
Maximum Tolerated Dose
Allosteric Regulation
Adult
Aged
Middle Aged
Uterine Cervical Neoplasms
Female
Male
Proto-Oncogene Proteins c-akt
Tandem Mass Spectrometry
Glycogen Synthase Kinase 3 beta
Research team
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Language
eng
Date accepted
2016-08-27
License start date
2016-11
Citation
European journal of cancer (Oxford, England : 1990), 2016, 68 pp. 1 - 10
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