Sarker, Debashis, Plummer, Ruth, Meyer, Tim, Sodergren, Mikael H, Basu, Bristi, Chee, Cheng Ean, Huang, Kai-Wen, Palmer, Daniel H 
ORCID: 0000-0002-7147-5703, Ting, Yuk, Evans, TR Jeff et al (show 26 more authors)
(2020)
MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-a, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.
CLINICAL CANCER RESEARCH, 26 (15).
pp. 3936-3946.
Abstract
<h4>Purpose</h4>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.<h4>Patients and methods</h4>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).<h4>Results</h4>Thirty-eight participants have been treated across six dose levels (28-160 mg/m<sup>2</sup>) 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.<h4>Conclusions</h4>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: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Carcinoma, Hepatocellular, Liver Neoplasms, CCAAT-Enhancer-Binding Proteins, Oligoribonucleotides, Antineoplastic Agents, Liposomes, Neoplasm Staging, Treatment Outcome, Infusions, Intravenous, Gene Expression Regulation, Neoplastic, Up-Regulation, Dose-Response Relationship, Drug, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Nanoparticles, Tumor Microenvironment |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 14 Jul 2021 08:27 |
| Last Modified: | 18 Jan 2023 21:36 |
| DOI: | 10.1158/1078-0432.CCR-20-0414 |
| Open Access URL: | https://eprints.gla.ac.uk/214604/ |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3129972 |
Dimensions
Dimensions
