Author: Sarker D.; Spicer J.; Hunter S.; Kwatra V.; Lloyd P.; Plummer R.; Meyer T.; Sodergren M.H. (mikael.sodergren@imperial.ac.uk); Basu B.; Chee C.E.; Huang K.-W.; Palmer D.H.; Ma Y.T.; Evans T.R.J.; Spalding D.R.C.; Pai M.; Sharma R.; Pinato D.J.; Nicholls J.P.; Reebye V.; Andrikakou P.; Collin D.; Nutbrown R.; Glenny H.; Fairbairn S.; Voutila J.; Dorman S.; Felstead S.; Vasara J.; Habib R.; Wood C.; Blakey D.C.; Habib N.; Saetrom P.; Huber H.E.; Rossi J.J.
Abstract: PURPOSE: Transcription factor C/EBP-alpha (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-alpha. 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). RESULT(S): Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) 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. CONCLUSION(S): 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-alpha and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
