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|Ref Type||Journal Article|
|Authors||Sarker D, Plummer R, Meyer T, Sodergren MH, Basu B, Chee CE, Huang KW, Palmer DH, Ma YT, Evans TRJ, Spalding DRC, Pai M, Sharma R, Pinato DJ, Spicer J, Hunter S, Kwatra V, Nicholls JP, Collin D, Nutbrown R, Glenny H, Fairbairn S, Reebye V, Voutila J, Dorman S, Andrikakou P, Lloyd P, Felstead S, Vasara J, Habib R, Wood C, Saetrom P, Huber HE, Blakey DC, Rossi JJ, Habib N|
|Title||MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 May 01|
|Abstract Text||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.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).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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CEBPA-51||MTL-CEBPA|NOV340 SMARTICLES|MTL-501||CEBPA-51 (MTL-CEBPA) is a small activating RNA that induces expression of CEBPA mRNA and protein, which subsequently leads to upregulation of albumin, and thereby potentially inhibiting cell growth (PMID: 28882451, PMID: 32357963).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||hepatocellular carcinoma||not applicable||CEBPA-51||Phase I||Actionable||In a Phase I trial, CEBPA-51 (MTL-CEBPA) treatment was well-tolerated and demonstrated manageable safety, and resulted in an objective response rate of 4% (1/24) in hepatocellular carcinoma patients with one partial response that lasted for 2 years, and stable disease as the best response in 12 patients, and resulted in a mean progression-free survival of 4.9 months (PMID: 32357963; NCT02716012).||32357963|
|Unknown unknown||hepatocellular carcinoma||not applicable||Lenvatinib||Case Reports/Case Series||Actionable||In a Phase I trial, a hepatocellular carcinoma patient treated with Lenvima (lenvatinib) following the discontinuation of CEBPA-51 (MTL-CEBPA) treatment achieved a partial response, but demonstrated progression at 6 months following treatment (PMID: 32357963; NCT02716012).||32357963|
|Unknown unknown||hepatocellular carcinoma||not applicable||Regorafenib||Case Reports/Case Series||Actionable||In a Phase I trial, two hepatocellular carcinoma patients treated with Stivarga (regorafenib) following the discontinuation of CEBPA-51 (MTL-CEBPA) treatment achieved stable disease 3 months following treatment, but the treatment was discontinued due to toxicity (PMID: 32357963; NCT02716012).||32357963|
|Unknown unknown||hepatocellular carcinoma||not applicable||Sorafenib||Case Reports/Case Series||Actionable||In a Phase I trial, three hepatocellular carcinoma patients treated with Nexavar (sorafenib) following CEBPA-51 (MTL-CEBPA) treatment achieved complete radiologic response (PMID: 32357963; NCT02716012).||32357963|