First-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-α in patients with advanced liver cancer.

Abstract

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.