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Published on: September 12, 2019
Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study
Michael Bitzer1, Marius Horger2, Edoardo G Giannini3
1Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany.
Background & Aims:
No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib.
Methods:
Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat.
Results:
57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival.
Conclusions:
The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications.
Lay Summary:
No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib.
Clinical Trial Registration:
The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.
Insights
This study found that combining resminostat with sorafenib is safe and effective for hepatocellular carcinoma patients progressing on sorafenib. Further research into ZFP64 as a biomarker is recommended.
Area of Science:
- Hepatocellular Carcinoma Research
- Pharmacology and Toxicology
- Biomarker Discovery
Background:
- No established therapies exist for hepatocellular carcinoma (HCC) patients progressing on first-line sorafenib.
- Histone deacetylase inhibitors offer a potential strategy to overcome therapy resistance in HCC.
Purpose of the Study:
- To investigate the safety, pharmacokinetics, and efficacy of resminostat, a histone deacetylase inhibitor, alone and in combination with sorafenib.
- To identify potential biomarkers for treatment response in HCC patients.
Main Methods:
- An exploratory, multi-center, open-label, phase I/II study involving 57 HCC patients with confirmed progression on sorafenib.
- Patients received either resminostat monotherapy or a combination of resminostat and sorafenib at various dose levels.
- Pharmacokinetics, safety, and efficacy endpoints including progression-free survival were assessed.
Main Results:
- The combination therapy was generally well-tolerated, with common adverse events including gastrointestinal disorders, thrombocytopenia, and fatigue.
- Progression-free survival at 12 weeks was 12.5% for resminostat monotherapy and 62.5% for the combination.
- Median time to progression and overall survival were significantly longer in the combination group (6.5 and 8.0 months) compared to monotherapy (1.8 and 4.1 months).
- Baseline expression of Zinc Finger Protein 64 (ZFP64) correlated with overall survival.
Conclusions:
- The combination of resminostat and sorafenib demonstrates early signs of efficacy and a favorable safety profile in advanced HCC patients.
- Sorafenib does not significantly alter the pharmacokinetics or histone deacetylase inhibitory activity of resminostat.
- ZFP64 warrants further investigation as a prognostic and potentially predictive biomarker for resminostat treatment in HCC and other cancers.
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