Your browser doesn't support javascript.
loading
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.
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.
Afiliación
  • Jamieson D; Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
  • Griffin MJ; Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
  • Sludden J; Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
  • Drew Y; 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.
  • Cresti N; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
  • Swales K; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
  • Merriman M; UCB, 216 Bath Road, Slough, SL1 4EN, UK.
  • Allen R; UCB, 216 Bath Road, Slough, SL1 4EN, UK.
  • Bevan P; WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
  • Buerkle M; WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
  • Mala C; WILEX AG, Grillparzerstr. 18, 81675, Munich, Germany.
  • Coyle V; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Northern Ireland Cancer Center, Belfast City Hospital, Belfast, UK.
  • Rodgers L; Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK.
  • Dean E; The Christie NHS Foundation Trust, The University of Manchester, Manchester, M20 4BX, UK.
  • Greystoke A; 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.
  • Banerji U; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, UK.
  • Wilson RH; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; Northern Ireland Cancer Center, Belfast City Hospital, Belfast, UK.
  • Evans TR; Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, G12 OYN, UK.
  • Anthoney A; St. James's Institute of Oncology, Beckett Street, Leeds, LS9 7TF, UK.
  • Ranson M; The Christie NHS Foundation Trust, The University of Manchester, Manchester, M20 4BX, UK.
  • Boddy AV; Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
  • Plummer R; 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.
Eur J Cancer ; 68: 1-10, 2016 11.
Article en En | MEDLINE | ID: mdl-27693888
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.
Asunto(s)
Neoplasias/tratamiento farmacológico; Inhibidores de Proteínas Quinasas/farmacología; Dolor Abdominal/inducido químicamente; Administración Oral; Adulto; Anciano; Regulación Alostérica; Anorexia/inducido químicamente; Neoplasias de los Conductos Biliares/tratamiento farmacológico; Neoplasias de los Conductos Biliares/metabolismo; Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico; Carcinoma de Pulmón de Células no Pequeñas/metabolismo; Colangiocarcinoma/tratamiento farmacológico; Colangiocarcinoma/metabolismo; Cromatografía Líquida de Alta Presión; Cromatografía Liquida; Neoplasias Colorrectales/tratamiento farmacológico; Neoplasias Colorrectales/metabolismo; Diarrea/inducido químicamente; Erupciones por Medicamentos/etiología; Neoplasias Esofágicas/tratamiento farmacológico; Neoplasias Esofágicas/metabolismo; Fatiga/inducido químicamente; Femenino; Glucógeno Sintasa Quinasa 3 beta/efectos de los fármacos; Glucógeno Sintasa Quinasa 3 beta/metabolismo; Humanos; Neoplasias Pulmonares/tratamiento farmacológico; Neoplasias Pulmonares/metabolismo; MAP Quinasa Quinasa 1/antagonistas & inhibidores; MAP Quinasa Quinasa 2/antagonistas & inhibidores; Masculino; Dosis Máxima Tolerada; Mesotelioma/tratamiento farmacológico; Mesotelioma/metabolismo; Persona de Mediana Edad; Proteína Quinasa 1 Activada por Mitógenos/efectos de los fármacos; Proteína Quinasa 1 Activada por Mitógenos/metabolismo; Proteína Quinasa 3 Activada por Mitógenos/efectos de los fármacos; Proteína Quinasa 3 Activada por Mitógenos/metabolismo; Náusea/inducido químicamente; Neoplasias/metabolismo; Neoplasias Pancreáticas/tratamiento farmacológico; Neoplasias Pancreáticas/metabolismo; Fosfoproteínas/efectos de los fármacos; Inhibidores de Proteínas Quinasas/efectos adversos; Inhibidores de Proteínas Quinasas/uso terapéutico; Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos; Proteínas Proto-Oncogénicas c-akt/metabolismo; Proteínas Quinasas S6 Ribosómicas 70-kDa/efectos de los fármacos; Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo; Espectrometría de Masas en Tándem
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Neoplasias Tipo de estudio: Etiology_studies Idioma: En Revista: Eur J Cancer Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Neoplasias Tipo de estudio: Etiology_studies Idioma: En Revista: Eur J Cancer Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido