A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2.
Clin Cancer Res
; 16(13): 3507-16, 2010 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-20472683
ABSTRACT
PURPOSE:
Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. EXPERIMENTALDESIGN:
Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional "3+3" design.RESULTS:
Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses.CONCLUSIONS:
The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
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Proteínas Proto-Oncogênicas c-met
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Receptor 2 de Fatores de Crescimento do Endotélio Vascular
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Inibidores de Proteínas Quinases
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Anilidas
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Neoplasias
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article