PMID- 29145039 OWN - NLM STAT- MEDLINE DCOM- 20171212 LR - 20180207 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 87 DP - 2017 Dec TI - A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification. PG - 131-139 LID - S0959-8049(17)31356-4 [pii] LID - 10.1016/j.ejca.2017.10.016 [doi] AB - 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/m(2)]) 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/m(2) 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/m(2), 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/m(2); SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01391533. CI - Copyright (c) 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Angevin, Eric AU - Angevin E AD - Drug Development Department, Departement d'Innovation Therapeutique et des Essais Precoces (DITEP), Universite Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: eric.angevin@gustaveroussy.fr. FAU - Spitaleri, Gianluca AU - Spitaleri G AD - Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: gianluca.spitaleri@ieo.it. FAU - Rodon, Jordi AU - Rodon J AD - Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, P. Vall d'Hebron 119-129, Barcelona, 08035, Spain. Electronic address: jrodon@vhio.net. FAU - Dotti, Katia AU - Dotti K AD - Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. Electronic address: katia.dotti@istitutotumori.mi.it. FAU - Isambert, Nicolas AU - Isambert N AD - Centre Georges-Francois Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: NIsambert@cgfl.fr. FAU - Salvagni, Stefania AU - Salvagni S AD - Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: stefania.salvagni@aosp.bo.it. FAU - Moreno, Victor AU - Moreno V AD - START MADRID - FJD., Hospital Universitario Fundacion Jimenez Diaz, vda. Reyes Catolicos, 2, 28040, Madrid, Spain. Electronic address: Victor.Moreno@start.stoh.com. FAU - Assadourian, Sylvie AU - Assadourian S AD - SANOFI, 54, Rue La Boetie, 75008 Paris, France. Electronic address: Sylvie.Assadourian@sanofi.com. FAU - Gomez, Corinne AU - Gomez C AD - SANOFI, 54, Rue La Boetie, 75008 Paris, France. Electronic address: Corinne.Gomez@sanofi.com. FAU - Harnois, Marzia AU - Harnois M AD - SANOFI, 54, Rue La Boetie, 75008 Paris, France. Electronic address: Marzia.Harnois@sanofi.com. FAU - Hollebecque, Antoine AU - Hollebecque A AD - Drug Development Department, Departement d'Innovation Therapeutique et des Essais Precoces (DITEP), Universite Paris-Saclay, Gustave Roussy, Villejuif, F-94805, France. Electronic address: Antoine.HOLLEBECQUE@gustaveroussy.fr. FAU - Azaro, Analia AU - Azaro A AD - Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, P. Vall d'Hebron 119-129, Barcelona, 08035, Spain. Electronic address: aazaro@vhio.net. FAU - Hervieu, Alice AU - Hervieu A AD - Centre Georges-Francois Leclerc, 1 Rue du Professeur Marion, 21000, Dijon, France. Electronic address: ahervieu@cgfl.fr. FAU - Rihawi, Karim AU - Rihawi K AD - Oncologia Medica, S. Orsola-Malpighi University Hospital Bologna, Via Pietro Albertoni, 15, 40138, Bologna, Italy. Electronic address: karim.rihawi@aosp.bo.it. FAU - De Marinis, Filippo AU - De Marinis F AD - Thoracic Oncology Division, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy. Electronic address: filippo.demarinis@ieo.it. LA - eng SI - ClinicalTrials.gov/NCT01391533 SI - ClinicalTrials.gov/NCT01391533 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20171114 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Antineoplastic Agents) RN - 0 (Benzothiazoles) RN - 0 (Biomarkers, Tumor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (SAR125844) RN - 8W8T17847W (Urea) RN - EC 2.7.10.1 (MET protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Benzothiazoles/*administration & dosage/adverse effects/pharmacokinetics MH - Biomarkers, Tumor/*antagonists & inhibitors/genetics/metabolism MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/genetics/pathology MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Europe MH - Female MH - *Gene Amplification MH - Humans MH - Lung Neoplasms/*drug therapy/enzymology/genetics/pathology MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/pharmacokinetics MH - Proto-Oncogene Proteins c-met/*antagonists & inhibitors/genetics/metabolism MH - Signal Transduction/drug effects MH - Time Factors MH - Treatment Outcome MH - United States MH - Urea/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics OTO - NOTNLM OT - Advanced solid tumours OT - Dose escalation OT - MET-amplified OT - MET-inhibitor OT - NSCLC OT - Phase I EDAT- 2017/11/18 06:00 MHDA- 2017/12/13 06:00 CRDT- 2017/11/18 06:00 PHST- 2017/10/13 00:00 [received] PHST- 2017/10/17 00:00 [accepted] PHST- 2017/11/18 06:00 [pubmed] PHST- 2017/12/13 06:00 [medline] PHST- 2017/11/18 06:00 [entrez] AID - S0959-8049(17)31356-4 [pii] AID - 10.1016/j.ejca.2017.10.016 [doi] PST - ppublish SO - Eur J Cancer. 2017 Dec;87:131-139. doi: 10.1016/j.ejca.2017.10.016. Epub 2017 Nov 14.