Background: MTL-CEBPA is a liposomal formulation of saRNA targeting the transcription factor C/EBP-α, which acts as a master regulator of liver homeostasis and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis and inhibits hepatocellular cancer (HCC) tumor growth in preclinical models. MTL-CEBPA is the first saRNA and the first drug targeting C/EBP-α entering clinical trials. Methods: Patients (pts) with advanced HCC (Child-Pugh A/B) or secondary liver cancer, were enrolled in a 3+3 dose escalation study. MTL-CEBPA is administered as a 1-hr IV infusion on Day 1, 8 and 15 of a 28 day cycle. The primary endpoint was safety and the secondary endpoints included PK, liver function improvement and anti-tumor activity. Correlative studies include C/EBP-α mRNA levels in PBMCs and tumor tissue, evaluation of C/EBP-α downstream target genes (e.g.TGFβ) and distal target engagement in WBCs (e.g.IL-6, NF-κB). Results: 19 participants have been treated across 5 dose levels (28-130 mg/m²): 13M/6F, median age 67 yrs (range 27 - 80), ECOG PS 0/1: 9/10. Tumour types include HCC (13), colorectal (4) and fibrolamellar (2). The most common treatment-related AEs (all grades/grade 3) include fatigue (9/1), diarrhoea (5/0), AST increase (5/1), low platelets (2/1) hyperbilirubinaemia (5/1) and hypophosphataemia (4/1). Maximum tolerated dose has not yet been reached. Serum PK analysis shows a terminal half life of > 24 hrs, with dose proportional C_max and AUC. Analysis of WBCs showed a significant increase of C/EBP-α expression during treatment providing evidence of target engagement. Of 10 evaluable pts with HCC, 4 pts have had SD≥ 4months, with one patient having an ongoing PR for 18 months associated with 73% decrease in tumour volume and reduction in IL-6, NF-κB and IFN-γ. Conclusions: Once weekly MTL-CEBPA therapy was well tolerated, shows promising PD and initial clinical response in patients with advanced HCC. Updated results for the dose escalation will be presented. Clinical trial information: NCT02716012