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

Sarker, D., Plummer, R., Meyer, T., Sodergren, M. H., Basu, B., Chee, C. E. and , (2020) 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. Clinical Cancer Research, 26(15), pp. 3936-3946. (doi: 10.1158/1078-0432.CCR-20-0414) (PMID:32357963)

Abstract

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 which up-regulates C/EBP-α. Experimental Design: We conducted a phase I, open label, dose escalation trial of MTL-CEBPA in adults with advanced HCC with cirrhosis, or resulting from non-alcoholic steatohepatitis (NASH) 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: 38 participants have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules. 34 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 3 schedules evaluated. Grade 3 treatment related adverse events occurred in 9 (24%) patients. In 24 HCC patients evaluable for efficacy, an objective tumour response was achieved in 1 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 (TKI); 3 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.

• Item Type: Articles
• Additional Information: Funding: This study was funded by MiNA Therapeutics. ClinicalTrials.gov ID: NCT02716012.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Evans, Professor Jeff
• Authors: Sarker, D., Plummer, R., Meyer, T., Sodergren, M. H., Basu, B., Chee, C. E., and ,
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 01 May 2020
• Copyright Holders: Copyright © 2020 American Association for Cancer Research
• First Published: First published in Clinical Cancer Research 26(15):3936-3946
• Publisher Policy: Reproduced in accordance with the publisher copyright policy