Sarker, DebashisDebashisSarkerPlummer, RuthRuthPlummerMeyer, TimTimMeyerSodergren, MikaelMikaelSodergrenBasu, BristiBristiBasuChee, Cheng EanCheng EanCheeKAI-WEN HUANGet al.,et al.2020-06-192020-06-192020-05-011078-0432https://scholars.lib.ntu.edu.tw/handle/123456789/503709Purpose: Transcription factor C/EBP-α (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-α. 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). Results: 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. Conclusions: 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-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC. Trial registration: ClinicalTrials.gov NCT02716012.en[SDGs]SDG3antineoplastic agent; CCAAT enhancer binding protein alpha; MTL CEBPA; sorafenib; unclassified drug; antineoplastic agent; CCAAT enhancer binding protein; CEBPA protein, human; liposome; nanoparticle; oligoribonucleotide; adult; aged; anemia; area under the curve; Article; ascites; clinical article; clinical outcome; cohort analysis; diarrhea; dizziness; drug distribution; drug dose escalation; drug efficacy; drug response; drug safety; drug withdrawal; dysgeusia; fatigue; female; fever; headache; hot flush; human; human cell; hyperbilirubinemia; hypertransaminasemia; hypoalbuminemia; hypophosphatemia; liver cell carcinoma; liver cirrhosis; liver metastasis; male; middle aged; minimum plasma concentration; multicenter study; multiple cycle treatment; nonalcoholic steatohepatitis; open study; phase 1 clinical trial; plasma clearance; plasma half life; priority journal; side effect; thrombocytopenia; upregulation; cancer staging; clinical trial; dose response; drug effect; gene expression regulation; genetics; intravenous drug administration; liver cell carcinoma; liver tumor; pathology; treatment outcome; tumor microenvironment; upregulation; very elderly; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Proteins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Infusions, Intravenous; Liposomes; Liver Neoplasms; Male; Middle Aged; Nanoparticles; Neoplasm Staging; Oligoribonucleotides; Treatment Outcome; Tumor Microenvironment; Up-Regulationjournal article10.1158/1078-0432.CCR-20-041432357963