MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

Autor:	Sarker D; King's College London, London, United Kingdom., Plummer R; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom., Meyer T; University College London Cancer Institute, London, United Kingdom., Sodergren MH; Department of Surgery and Cancer, Imperial College London, London, United Kingdom. mikael.sodergren@imperial.ac.uk nagy.habib@imperial.ac.uk nagy@minatx.com., Basu B; Addenbrooke's Hospital, Cambridge, United Kingdom., Chee CE; National University Cancer Institute Singapore, Singapore., Huang KW; National Taiwan University Hospital, Taipei, Taiwan., Palmer DH; Department of Molecular and Clinical Cancer Medicine, University of Liverpool and Clatterbridge Cancer Centre, Liverpool, United Kingdom., Ma YT; University of Birmingham, Birmingham, United Kingdom., Evans TRJ; University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom., Spalding DRC; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Pai M; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Sharma R; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Pinato DJ; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Spicer J; King's College London, London, United Kingdom., Hunter S; King's College London, London, United Kingdom., Kwatra V; King's College London, London, United Kingdom., Nicholls JP; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; MiNA Therapeutics Ltd., London, United Kingdom., Collin D; MiNA Therapeutics Ltd., London, United Kingdom., Nutbrown R; MiNA Therapeutics Ltd., London, United Kingdom., Glenny H; MiNA Therapeutics Ltd., London, United Kingdom., Fairbairn S; MiNA Therapeutics Ltd., London, United Kingdom., Reebye V; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; MiNA Therapeutics Ltd., London, United Kingdom., Voutila J; MiNA Therapeutics Ltd., London, United Kingdom., Dorman S; MiNA Therapeutics Ltd., London, United Kingdom., Andrikakou P; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Lloyd P; King's College London, London, United Kingdom., Felstead S; MiNA Therapeutics Ltd., London, United Kingdom., Vasara J; MiNA Therapeutics Ltd., London, United Kingdom., Habib R; MiNA Therapeutics Ltd., London, United Kingdom., Wood C; MiNA Therapeutics Ltd., London, United Kingdom., Saetrom P; Department of Clinical and Molecular Medicine, Department of Computer and Information Science, Bioinformatics Core Facility-BioCore, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, NTNU, Trondheim, Norway., Huber HE; BioTD Strategies LLC, Lansdale, Pennsylvania., Blakey DC; MiNA Therapeutics Ltd., London, United Kingdom., Rossi JJ; Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California., Habib N; Department of Surgery and Cancer, Imperial College London, London, United Kingdom. mikael.sodergren@imperial.ac.uk nagy.habib@imperial.ac.uk nagy@minatx.com.; MiNA Therapeutics Ltd., London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Aug 01; Vol. 26 (15), pp. 3936-3946. Date of Electronic Publication: 2020 May 01.
DOI:	10.1158/1078-0432.CCR-20-0414
Abstrakt:	Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. Patients and Methods: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). Results: Thirty-eight participants have been treated across six dose levels (28-160 mg/m 2 ) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. Conclusions: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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