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dc.contributor.authorJamieson, Den_US
dc.contributor.authorGriffin, MJen_US
dc.contributor.authorSludden, Jen_US
dc.contributor.authorDrew, Yen_US
dc.contributor.authorCresti, Nen_US
dc.contributor.authorSwales, Ken_US
dc.contributor.authorMerriman, Men_US
dc.contributor.authorAllen, Ren_US
dc.contributor.authorBevan, Pen_US
dc.contributor.authorBuerkle, Men_US
dc.contributor.authorMala, Cen_US
dc.contributor.authorCoyle, Ven_US
dc.contributor.authorRodgers, Len_US
dc.contributor.authorDean, Een_US
dc.contributor.authorGreystoke, Aen_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorWilson, RHen_US
dc.contributor.authorEvans, TRen_US
dc.contributor.authorAnthoney, Aen_US
dc.contributor.authorRanson, Men_US
dc.contributor.authorBoddy, AVen_US
dc.contributor.authorPlummer, Ren_US
dc.date.accessioned2017-03-24T14:17:18Z
dc.date.issued2016-09-28en_US
dc.identifier.citationEuropean journal of cancer (Oxford, England : 1990), 2016, 68 pp. 1 - 10en_US
dc.identifier.issn0959-8049en_US
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.abstractWe 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.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1 - 10en_US
dc.languageengen_US
dc.language.isoengen_US
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.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-08-27en_US
rioxxterms.versionofrecord10.1016/j.ejca.2016.08.026en_US
rioxxterms.licenseref.startdate2016-09-28en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfEuropean journal of cancer (Oxford, England : 1990)en_US
pubs.notesNot knownen_US
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/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 Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.volume68en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
dc.contributor.icrauthorBanerji, Udaien_US
dc.contributor.icrauthorTurner, Lydiaen_US


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