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@article{Sarker:2020:10.1158/1078-0432.CCR-20-0414,
author = {Sarker, D and Plummer, R and Meyer, T and Sodergren, MH and Basu, B and Chee, CE and Huang, K-W and Palmer, DH and Ma, YT and Evans, TRJ and Spalding, DRC and Pai, M and Sharma, R and Pinato, DJ and Spicer, J and Hunter, S and Kwatra, V and Nicholls, JP and Collin, D and Nutbrown, R and Glenny, H and Fairbairn, S and Reebye, V and Voutila, J and Dorman, S and Andrikakou, P and Lloyd, P and Felstead, S and Vasara, J and Habib, R and Wood, C and Saetrom, P and Huber, HE and Blakey, DC and Rossi, JJ and Habib, N},
doi = {10.1158/1078-0432.CCR-20-0414},
journal = {Clinical Cancer Research},
pages = {3936--3946},
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},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-20-0414},
volume = {26},
year = {2020}
}

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TY  - JOUR
AB  - PURPOSE: 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.
AU  - Sarker,D
AU  - Plummer,R
AU  - Meyer,T
AU  - Sodergren,MH
AU  - Basu,B
AU  - Chee,CE
AU  - Huang,K-W
AU  - Palmer,DH
AU  - Ma,YT
AU  - Evans,TRJ
AU  - Spalding,DRC
AU  - Pai,M
AU  - Sharma,R
AU  - Pinato,DJ
AU  - Spicer,J
AU  - Hunter,S
AU  - Kwatra,V
AU  - Nicholls,JP
AU  - Collin,D
AU  - Nutbrown,R
AU  - Glenny,H
AU  - Fairbairn,S
AU  - Reebye,V
AU  - Voutila,J
AU  - Dorman,S
AU  - Andrikakou,P
AU  - Lloyd,P
AU  - Felstead,S
AU  - Vasara,J
AU  - Habib,R
AU  - Wood,C
AU  - Saetrom,P
AU  - Huber,HE
AU  - Blakey,DC
AU  - Rossi,JJ
AU  - Habib,N
DO  - 10.1158/1078-0432.CCR-20-0414
EP  - 3946
PY  - 2020///
SN  - 1078-0432
SP  - 3936
TI  - 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
T2  - Clinical Cancer Research
UR  - http://dx.doi.org/10.1158/1078-0432.CCR-20-0414
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32357963
UR  - https://clincancerres.aacrjournals.org/content/26/15/3936
UR  - http://hdl.handle.net/10044/1/81948
VL  - 26
ER  -

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