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 sorafenibtreatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostatand a combination therapy with resminostatand sorafenib. Methods Patients with HCC and radiologically confirmed progression on sorafenibwere 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 resminostatplus 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 deacetylaseinhibition and highest increase in H4-acetylation matched T max of resminostat. Sorafenibor the Child-Pugh scoredid 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 resminostatand 62.5% for resminostatplus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostatand 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 sorafeniband resminostatin HCC patients was safe and showed early signs of efficacy. Sorafenibdid not alter the pharmacokinetic profile of resminostator its histone deacetylaseinhibitory activity in vivo . A prognostic and potentially predictive role of ZFP64 for treatment with resminostatshould 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 sorafenibcurrently exists. Epigenetic modulation by inhibition of histone deacetylasesmight be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenibinvestigated the histone deacetylases inhibitor resminostatas 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.