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dc.contributor.authorJamieson, D
dc.contributor.authorGriffin, MJ
dc.contributor.authorSludden, J
dc.contributor.authorDrew, Y
dc.contributor.authorCresti, N
dc.contributor.authorSwales, K
dc.contributor.authorMerriman, M
dc.contributor.authorAllen, R
dc.contributor.authorBevan, P
dc.contributor.authorBuerkle, M
dc.contributor.authorMala, C
dc.contributor.authorCoyle, V
dc.contributor.authorRodgers, L
dc.contributor.authorDean, E
dc.contributor.authorGreystoke, A
dc.contributor.authorBanerji, U
dc.contributor.authorWilson, RH
dc.contributor.authorEvans, TRJ
dc.contributor.authorAnthoney, A
dc.contributor.authorRanson, M
dc.contributor.authorBoddy, AV
dc.contributor.authorPlummer, R
dc.date.accessioned2017-03-24T14:17:18Z
dc.date.issued2016-11
dc.identifier.citationEuropean journal of cancer (Oxford, England : 1990), 2016, 68 pp. 1 - 10
dc.identifier.issn0959-8049
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/495
dc.identifier.eissn1879-0852en_US
dc.identifier.doi10.1016/j.ejca.2016.08.026en_US
dc.description.abstractPurpose 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.
dc.formatPrint-Electronic
dc.format.extent1 - 10
dc.languageeng
dc.language.isoeng
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectMesothelioma
dc.subjectCholangiocarcinoma
dc.subjectCarcinoma, Non-Small-Cell Lung
dc.subjectBile Duct Neoplasms
dc.subjectEsophageal Neoplasms
dc.subjectColorectal Neoplasms
dc.subjectPancreatic Neoplasms
dc.subjectLung Neoplasms
dc.subjectDrug Eruptions
dc.subjectFatigue
dc.subjectAbdominal Pain
dc.subjectAnorexia
dc.subjectDiarrhea
dc.subjectNausea
dc.subjectMAP Kinase Kinase 1
dc.subjectMAP Kinase Kinase 2
dc.subjectMitogen-Activated Protein Kinase 1
dc.subjectMitogen-Activated Protein Kinase 3
dc.subjectRibosomal Protein S6 Kinases, 70-kDa
dc.subjectPhosphoproteins
dc.subjectProtein Kinase Inhibitors
dc.subjectChromatography, Liquid
dc.subjectChromatography, High Pressure Liquid
dc.subjectAdministration, Oral
dc.subjectMaximum Tolerated Dose
dc.subjectAllosteric Regulation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectUterine Cervical Neoplasms
dc.subjectFemale
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectTandem Mass Spectrometry
dc.subjectGlycogen Synthase Kinase 3 beta
dc.titleA phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.
dc.typeJournal Article
dcterms.dateAccepted2016-08-27
rioxxterms.versionofrecord10.1016/j.ejca.2016.08.026
rioxxterms.licenseref.startdate2016-11en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEuropean journal of cancer (Oxford, England : 1990)
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.publication-statusPublished
pubs.volume68en_US
pubs.embargo.termsNot known
icr.researchteamClinical PD Biomarker Groupen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
dc.contributor.icrauthorSwales, Karenen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorTurner, Lydiaen


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