CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib, in advanced/metastatic non-small cell lung cancer.
Br J Cancer
; 109(11): 2803-9, 2013 Nov 26.
Article
em En
| MEDLINE
| ID: mdl-24169346
ABSTRACT
BACKGROUND:
A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population.METHODS:
Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs.RESULTS:
Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ≥3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (≥24 weeks) were reported.CONCLUSION:
Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype 360 mg BID for EMs and 240 mg BID for PMs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinonas
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Quinazolinas
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Quinolinas
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Hidrocarboneto de Aril Hidroxilases
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Protocolos de Quimioterapia Combinada Antineoplásica
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Carcinoma Pulmonar de Células não Pequenas
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Inibidores de Proteínas Quinases
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Neoplasias Pulmonares
Tipo de estudo:
Clinical_trials
Limite:
Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article