2878 - First-in-human, first-in-class phase I study of MTL-CEBPA, a RNA oligonucleotide targeting the myeloid cell master regulator C/EBP-_, in patients with advanced hepatocellular cancer (HCC)

Background

MTL-CEBPA is a first-in-class small activating RNA (saRNA) oligonucleotide which specifically up-regulates the myeloid cell master regulator, C/EBP-α (CCAAT/enhancer-binding protein alpha).

Methods

We conducted a phase I, 3 + 3 dose escalation and dose expansion trial of MTL-CEBPA in adults with HCC or secondary liver cancer. Patients received intravenous MTL-CEBPA at 28-160 mg/m2 for 3 weeks either QW, BIW at d1 and d2, BIW at d1 and d3, or TIW at d1, d2, and d3 followed by a rest period of 1 week. Adverse events (AEs), serum PK, WBC biomarkers and anti-tumour activity were assessed.

Results

38 participants (31 HCC, 4 colorectal, 2 fibrolamellar, 1 ampullary) have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules: 29M/9F, median age 66 years (range 27 - 80), ECOG PS 0/1: 16/22. In 28 HCC patients evaluable for efficacy, PR was achieved in 1 pt, SD > 1 year in 1 patient and SD < 1 year in 11 pts. After discontinuation of MTL-CEBPA, four sorafenib- naïve HCC patients were treated with sorafenib; 3/4 had durable CR (14, 12 and 9 months) and 1/4 had PR [6 months] by RECIST 1.1. Treatment-related adverse events (all grades) that occurred in more than 10% of patients were fatigue (23.7%), thrombocytopaenia (13.2%), anaemia (13.2%), elevated AST (13.2%), elevated ALP (10.5%), hypoalbuminaemia (10.5%), increased ALT (10.5%) and increased bilirubin (10.5%); no maximum dose was reached in any dosing cohorts. Target engagement was evidenced in evaluable patients by a significant 1.5 fold increase in CEBPA mRNA in WBC and a significant increase in WBC count consistent with C/EBP-α dependent granulopoiesis. Altered immunological markers were observed in WBC of one patient including decreased levels of ADA, PD-L1 and CXCR4 mRNA.

Conclusions

MTL-CEBPA is a first-in-class therapy targeting the myeloid cell master regulator C/EBP-α. In HCC patients MTL-CEBPA demonstrated a good safety profile, induced altered gene expression in WBC and as well as anti-tumour activity. These encouraging phase I data validate targeting of CEBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Clinical trial identification

NCT02716012.

Editorial acknowledgement

Legal entity responsible for the study

MiNA Therapeutics.

Funding

MiNA Therapeutics.

Disclosure

D. Sarker: Travel / Accommodation / Expenses: MiNA Therapeutics; Honoraria (self): MSD; Honoraria (self): EISAI; Honoraria (self): BAYER; Honoraria (self), Travel / Accommodation / Expenses: IPSEN. K. HUANG: Research grant / Funding (self): MiNA Therapeutics. N. Habib: Shareholder / Stockholder / Stock options: MiNA Therapeutics. All other authors have declared no conflicts of interest.