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4601 Background: MTL-CEBPA is the first small activating RNA to enter clinical trials and upregulates C/EBPα, a master regulator of myeloid cell differentiation. We previously reported a favourable safety profile of MTL-CEBPA as a single agent in HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, 3 out of 5 patients (pts) treated with sorafenib off study had a complete response (CR) of 7-18 months duration; 2 pts of which demonstrated resolution of lung metastases for > 1 year. Here we provide new data on pts prospectively treated with MTL-CEBPA + sorafenib. Methods: Primary objective was to assess safety and tolerability of MTL-CEBPA 90-130mg/m2 QW or BIW in combination with sorafenib 400mg BD administered to HCC patients either concomitantly or sequentially, in cohorts either tyrosine kinase inhibitor (TKI) naive or resistant. Secondary objectives included preliminary assessment of activity by response rate (RECIST v1.1) and immune landscape analysis. Results: As at the cut off date of 1 Feb 2020, 12 pts have been treated with MTL-CEBPA co-administered with sorafenib and 14 pts with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3-4) in these groups include facial flushing (4/0), raised AST (4/2) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). Of 14 evaluable pts in the TKI naive cohorts, 2 pts had CR, 3 pts had partial response and 7 had stable disease. 9/10 pts in the TKI resistant cohorts evaluable for efficacy had stable disease. Flow cytometry demonstrated statistically significant decreases in frequency of immature CD66+CD10− neutrophils and myeloid derived suppressor cells. IHC demonstrated significant reduction in M2 macrophages in tumour biopsies. Conclusions: MTL-CEBPA + sorafenib is well tolerated with an acceptable safety profile. This study has confirmed signals of objective response to the combination treatment in TKI naïve HCC patients with viral aetiology, warranting expanded development in these patients. Updated efficacy and safety data will be presented. Clinical trial information: NCT02716012. [Table: see text]

554 Background: MTL-CEBPA is the first saRNA to enter clinical trials and targets the transcription factor C/EBPα, a master regulator of myeloid cell differentiation. We have previously reported a favourable safety profile of MTL-CEBPA given as a single agent QWx3 every 28 days, in patients with HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, three out of five patients treated with sorafenib off study have had maintained complete radiological response (CR) of 7-18 months duration; 2 patients demonstrated resolution of lung metastases > 1 year. Here we provide updated data on phase 1 patients treated with sorafenib off study as well as subsequent combination cohorts. Methods: MTL-CEBPA 130mg/m2 QWx3 or BIW and sorafenib 400mg bd were administered to patients with HCC using combination or sequential dosing regimens, in cohorts either tyrosine kinase inhibitor naive or resistant. On treatment liver biopsies evaluated changes in M2 macrophages (CD163). Flow cytometry of peripheral blood determined changes in myeloid cell populations. Results: 12 patients have been treated with MTL-CEBPA co-administered with sorafenib and 14 patients treated with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3) in this group include facial flushing (4/0), raised AST (3/1) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). 1 TKI naïve patient in the co-administration cohort has maintained CR at 7 months and two patients have SD (ongoing at 3 & 4 months both in sequential cohort). IHC in the patient with CR has demonstrated 95% reduction in M2 macrophages with significant decrease in frequency of immature CD10- neutrophils (-85.7%; p = 0.0078), PMN-MDSCs (-49.3%; p = 0.00145) and M-MDSCs (-18.4%; P = 0.0072). All responding patients have underlying HBV or HCV. Conclusions: MTL-CEBPA is a novel saRNA targeting myeloid cells which may result in a significantly enhanced oncological response in HCC of viral aetiology. Updated safety and efficacy data will be presented. Clinical trial information: NCT02716012.

2509Background: 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 incl...

TPS2612 Background: saRNAs are small oligonucleotide drugs designed to selectively upregulate therapeutic proteins by recruiting endogenous transcriptional complexes to a target gene, leading to increased expression of naturally processed mRNA. Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) is a leucine zipper protein which acts as a master regulator of liver homeostasis and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis. MTL-CEBPA comprises a double stranded RNA payload formulated inside a SMARTICLES liposomal nanoparticle to specifically target the CEBPA gene and has been shown to improve liver function and inhibit hepatocellular cancer (HCC) tumor growth in preclinical models (Reebye et al, Hepatology, 2014). MTL-CEBPA is the first saRNA and the first drug targeting C/EBP-α to enter clinical trials. Methods: Pts with advanced HCC (Child-Pugh A or B7 only) or secondary liver cancer refractory to or ineligible for standard treatment, ECOG PS 0-1, acceptable haematologic, liver and renal function, are currently being enrolled in a standard 3+3 dose escalation study. Once the RP2D is defined, 12-15 patients with advanced HCC will be evaluated further in a dose expansion cohort. MTL-CEBPA is administered as a 1-hr IV infusion on Day 1, 8 and 15 of a 28-day cycle. RECIST tumor response is assessed after every 2 cycles. The primary objective is to determine safety and tolerability; secondary objectives include PK, liver function improvement and anti-tumor activity. Correlative studies include C/EBP-α mRNA levels in PBMCs and optional tumor tissue, evaluation of C/EBP-α downstream target genes (e.g.TGFβ) and distal target engagement in white blood cells (e.g.IL-6, NF-κB, IFN-γ). Recruitment to cohort 2 is shortly to be completed, with no DLTs reported to date. Clinical trial information: NCT02716012.