• Eur. J. Cancer · Dec 2017

    Multicenter Study

    A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

    • Eric Angevin, Gianluca Spitaleri, Jordi Rodon, Katia Dotti, Nicolas Isambert, Stefania Salvagni, Victor Moreno, Sylvie Assadourian, Corinne Gomez, Marzia Harnois, Antoine Hollebecque, Analia Azaro, Alice Hervieu, Karim Rihawi, and Filippo De Marinis.
    • Drug Development Department, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Université Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: eric.angevin@gustaveroussy.fr.
    • Eur. J. Cancer. 2017 Dec 1; 87: 131-139.

    PurposeDysregulated 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.MethodsThis 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.ResultsIn 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.ConclusionThe 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 NumberNCT01391533.Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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