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.
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.



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.



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.



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.
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
David
D
Jamieson
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Melanie J
MJ
Griffin
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Julieann
J
Sludden
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
Yvette
Y
Drew
Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
Nicola
N
Cresti
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
Karen
K
Swales
UCB, 216 Bath Road, Slough, SL1 4EN, UK.
Mark
M
Merriman
UCB, 216 Bath Road, Slough, SL1 4EN, UK.
Rodger
R
Allen
WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
Paul
P
Bevan
WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
Markus
M
Buerkle
WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
Carola
C
Mala
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Northern Ireland Cancer Center, Belfast City Hospital, Belfast, UK.
Vicky
V
Coyle
Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK.
Lisa
L
Rodgers
The Christie NHS Foundation Trust, The University of Manchester, Manchester, M20 4BX, UK.
Emma
E
Dean
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
Alastair
A
Greystoke
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
Udai
U
Banerji
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Northern Ireland Cancer Center, Belfast City Hospital, Belfast, UK.
Richard H
RH
Wilson
Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK.
T R Jeffery
TR
Evans
St. James's Institute of Oncology, Beckett Street, Leeds, LS9 7TF, UK.
Alan
A
Anthoney
The Christie NHS Foundation Trust, The University of Manchester, Manchester, M20 4BX, UK.
Malcolm
M
Ranson
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Alan V
AV
Boddy
Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. Electronic address: ruth.plummer@ncl.ac.uk.
Ruth
R
Plummer
D015746:Abdominal Pain / Q000139:chemically induced; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000494:Allosteric Regulation; D000855:Anorexia / Q000139:chemically induced; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D003875:Drug Eruptions / Q000209:etiology; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism
D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
MEK inhibitor; Optimal biological dose; Pharmacodynamics; Pharmacokinetics; Phase I