A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.
Eur J Cancer
; 87: 131-139, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-29145039
ABSTRACT
PURPOSE:
Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation.METHODS:
This was a phase I dose-escalation (3 + 3 design [50-740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort.RESULTS:
In total, 72 patients were enrolled dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number.CONCLUSION:
The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER NCT01391533.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ureia
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Biomarcadores Tumorais
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Amplificação de Genes
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Carcinoma Pulmonar de Células não Pequenas
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Proteínas Proto-Oncogênicas c-met
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Inibidores de Proteínas Quinases
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Benzotiazóis
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Neoplasias Pulmonares
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Antineoplásicos
Tipo de estudo:
Clinical_trials
País/Região como assunto:
America do norte
/
Europa
Idioma:
En
Revista:
Eur J Cancer
Ano de publicação:
2017
Tipo de documento:
Article