1区 · 医学
Article
作者: Dorman, Stephanie ; Huber, Hans E. ; Glenny, Helen ; Rossi, John J. ; Evans, T.R. Jeff ; Lloyd, Peter ; Andrikakou, Pinelopi ; Habib, Nagy ; Pai, Madhava ; Meyer, Tim ; Voutila, Jon ; Sarker, Debashis ; Sodergren, Mikael H. ; Habib, Robert ; Huang, Kai-Wen ; Saetrom, Pal ; Vasara, Jenni ; Wood, Chris ; Basu, Bristi ; Sharma, Rohini ; Palmer, Daniel H. ; Nicholls, Joanna P. ; Spalding, Duncan R.C. ; Ma, Yuk Ting ; Hunter, Sarah ; Nutbrown, Robert ; Kwatra, Vineet ; Blakey, David C. ; Felstead, Steve ; Chee, Cheng Ean ; Fairbairn, Sonia ; Collin, David ; Pinato, David J. ; Spicer, James ; Reebye, Vikash ; Plummer, Ruth
AbstractPurpose: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.