Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma – The SHELTER study

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 600 mg resminostat plus 400 to 800 mg sorafenib. The monotherapy group (n = 19) received 600 mg 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 T_max 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 (12 weeks, 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 4.1 months for resminostat and 6.5 and 8.0 months 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.

Introduction

With globally approximately 750,000 new cases of hepatocellular carcinoma (HCC) per year, primary cancer of the liver is the second leading cause of cancer-related deaths worldwide [1]. For HCC patients with advanced disease, the kinase inhibitor sorafenib (Nexavar®) is currently the only approved drug, providing a median time to radiologic progression (TTP) of 5.5 months and an overall survival (OS) of 10.7 months [2]. However, many tumors are either primarily resistant to sorafenib or develop drug resistance during therapy. Since a number of other kinase inhibitors including sunitinib [3], linifanib [4], and brivanib [5], [6] have shown limited benefit in clinical studies, a high medical need exists to identify new drugs that employ alternative mechanisms of action in HCC.

Epigenetic changes play an important role in the pathogenesis of HCC [7], [8]. High histone deacetylase (HDAC) expression correlates with higher incidences of HCC, cell invasion into the portal vein, poorer histological differentiation, a more advanced TNM stage and lower survival rates after surgical resection [9]. Recent evidence suggests that acquisition of drug tolerance and resistance against anti-cancer agents is at least partly mediated by epigenetic mechanisms, such as histone deacetylation [10]. Inhibition of HDACs may revert chromatin modifications in tumor cells and restore sensitivity towards previously inefficient drugs. HDAC inhibitors have promising preclinical and clinical anti-tumor activity in HCC [11], [12], [13], [14] and their further exploration might prove an attractive concept to overcome drug tolerance and therapy resistance in sorafenib pretreated patients.

In this exploratory phase I/II study advanced HCC patients with radiologically confirmed progression on first-line treatment with sorafenib were recruited. The study investigated safety, pharmacokinetics and early evidence of efficacy of the HDAC inhibitor resminostat [15] as single agent or in combination with sorafenib (phase II part of the study) and included a dose escalation phase for the combination (phase I part). The study was accompanied by an exploratory biomarker program, including gene expression analyses in peripheral blood cells, to identify biomarkers that might offer correlation to clinical responsiveness to resminostat, that could guide a personalized treatment approach for patients with HCC.