Z Gastroenterol 2010; 48 - P432
DOI: 10.1055/s-0030-1263872

First clinical data of resminostat, a novel oral histone deacetylase (HDAC) inhibitor, in patients with hepatocellular carcinoma (HCC) – the SHELTER Study

M Bitzer 1, M Horger 2, M Ebert 3, T Ganten 4, M Wörns 5, B Hauns 6, A Mais 6, R Jankowsky 6, B Hentsch 6, UM Lauer 1
  • 1Medizinische Universitätsklinik Tübingen, Innere Medizin I, Tübingen, Germany
  • 2University of Tübingen, Department of Diagnostic Radiology, Tübingen, Germany
  • 3Klinikum rechts der Isar der TU München, II. Medizinische Klinik, München, Germany
  • 4Medizinische Universitätsklinik Heidelberg, Innere Medizin IV, Heidelberg, Germany
  • 5Medizinische Universitätsklinik und Poliklinik Mainz, I. Medizinische Klinik, Mainz, Germany
  • 64SC AG, Planegg-Martinsried, Germany

Aims: Resminostat (4SC-201) is a novel specific pan-HDAC inhibitor under clinical evaluation as mono or combination therapy for solid and hematological malignancies. Here, we describe the first results of a phase II study being started in 2009 to evaluate the safety, tolerability and efficacy of resminostat in patients with HCC exhibiting progressive disease under sorafenib first-line therapy.

Methods: Patients with advanced stage HCC, BCLC classes B or C are included in a multi-center, open-label, two-arm parallel group trial. Arm A consists of a combination treatment of resminostat and sorafenib with escalating dose levels to evaluate potential dose-limiting toxicities (DLT) and the maximum tolerated dose. Patients in Arm B receive resminostat alone (600mg) in 14-day cycles each consisting of 5 consecutive treatment days (D1–5) followed by a 9-day rest period. Primary objective is to determine the progression-free-survival rate after 12 weeks (6 treatment cycles). Secondary objectives include safety and tolerability parameters, tumor response, assessment of pharmacokinetics and biomarkers.

Results: To date, 9 pts were treated either with resminostat alone or in the combination arm with sorafenib at the first two dose levels consisting of 200mg or 400mg resminostat (D1–5, once daily) and sorafenib 400mg (continuous, twice daily). The majority of adverse events include gastrointestinal disorders such as nausea and vomiting; these symptoms ranged from mild to moderate intensity. The most prominent adverse event was a skin reaction of grade 2 seen under the combination. Up to now, there were no DLT, defined as grade 4 hematological toxicity or grade 3/4 non-hematological toxicity occurring in the first cycle. Following repeated dose administration, high plasma exposure of resminostat was obtained indicating good bioavailability and consistency with phase I data.

Conclusions: Preliminary clinical data confirmed the favorable oral drug profile and good tolerability of resminostat either in mono- or in combination treatment with sorafenib. Updated data of this clinically ongoing study will be presented at the meeting.