4SC AG, the German drug discovery and development company, announced the dosing of the first patient in its phase-II trial with 4SC-201 (resminostat), a pan-histone deacetylase (HDAC) inhibitor, as a new potential treatment option for patients with advanced hepatocellular carcinoma (HCC), the most frequent form of liver cancer. This proof-of-concept (POC) study will evaluate 4SC-201 as a second line therapy in this indication, for which only a single first line therapy drug is currently approved.

The 'Shelter' study, entitled 'A proof-of-concept phase-II study to evaluate efficacy, safety and pharmacokinetics of 4SC-201 and of the treatment combination of sorafenib plus 4SC-201 in patients with hepatocellular carcinoma exhibiting progressive disease under sorafenib treatment', will examine whether treatment with 4SC-201 alone or in combination with sorafenib (Nexavar, the current standard of care in advanced HCC), can induce progression free survival and tumour responses in HCC patients who display progressive disease under treatment with sorafenib. This two-arm, proof-of-concept study will be performed at oncology-experienced university hospitals in Germany.

In the first study arm 15 patients will be treated with the maximum tolerated dose of the combination therapy which will be determined through an initial dose-escalation part, testing sorafenib in combination with 200mg to 600mg of 4SC-201. In the second study arm 15 patients will discontinue sorafenib treatment prior to inclusion into the study and will receive 600mg of 4SC-201 as a monotherapy. In both arms 4SC-201 will be applied orally once daily over five consecutive days, followed by a nine day 4SC-201-treatment free period. In the combination arm sorafenib is additionally administered continuously every day. In both study arms, the resulting 14 day cycle for the treatment with 4SC-201 (a '5 + 9' dosing schedule) will be repeated until there is evidence of progressive disease.

The first two radiological tumour stagings will be performed after six and 12 weeks. Patients who experience a clinical benefit, eg, a stabilisation of their progressive disease or tumour regression, will be offered the opportunity to extend the study treatment until disease progression occurs or until the patient voluntarily withdraws. Based on the data of the first 15 patients treated in each study arm, an optional extension phase comprising ten additional patients may be included into each study arm. The primary endpoint of the study is to determine the progression free survival rate (PFSR) after twelve weeks of study treatment. The secondary endpoints include the analysis of time-to- progression (TTD), PFSR estimated at six weeks and PFSR estimated beyond twelve weeks of treatment, overall survival, analysis of drug safety, tolerability, pharmacokinetics and the investigation of biomarkers.

In preclinical studies 4SC-201 was shown to be very potent in inhibiting the growth of different liver cancer cells, and also displayed synergistic activity on liver cancer cell growth when combined with sorafenib.

Professor Dr Michael Bitzer, the coordinating investigator from the University Hospital Tübingen, Germany, commented, "Advanced HCC is an aggressive form of cancer in which classical chemotherapy approaches fail, despite huge scientific efforts over decades. Only the recent approval of a targeted therapy sorafenib, the only approved therapy for the systemic treatment for advanced HCC, has offered an innovative approach to treat these patients. However, there is an unmet medical need for new therapeutic approaches for patients that do not tolerate, or have disease progression whilst under sorafenib treatment. Notably, this need is in the second line setting where there is currently no other approved treatment option. Based on preclinical and phase-I data generated by 4SC-201 (resminostat), we are hopeful that this HDAC inhibitor may offer considerable clinical benefit to HCC patients that are progressive under treatment with the only currently approved therapy."

Dr Bernd Hentsch, chief development officer at 4SC commented, "We are very excited about commencing this proof-of-concept study for 4SC-201 (resminostat) in HCC, the first tumour disease to test the clinical efficacy of our lead oncology candidate. We have selected this indication as we believe that 4SC-201, based on our Phase I data, has the potential to stop tumour progression. We will investigate tumour responses in patients receiving monotherapy treatment with 4SC-201, and also after combination treatment, in which we will be able to additionally determine whether 4SC-201-can induce a re-sensitisation to treatment with sorafenib. Our new therapy option 4SC-201 could potentially offer tumour regression or a stabilised disease state, with the aim of moving these patients towards disease control." Additional information about the clinical trial can be found at www.clinicaltrials.gov.

4SC-201 is an oral, pan-isotope histone deacetylase (HDAC) inhibitor, for which recently the INN 'Resminostat' has been proposed by the WHO.