Z Gastroenterol 2012; 50 - P5_06
DOI: 10.1055/s-0031-1295962

Combination Treatment of Sorafenib and Resminostat, a new HDAC Inhibitor, in Patients with Sorafenib-resistant Hepatocellular Carcinoma (HCC) – Results of the Dose-Escalation Phase

M Bitzer 1, M Horger 2, TM Ganten 3, J Siveke 4, MA Woerns 5, M Dollinger 6, G Gerken 7, ME Scheulen 8, H Wege 9, A Mais 10, R Jankowsky 10, B Hauns 10, B Hentsch 10, UM Lauer 1
  • 1Gastroenterologie, Hepatologie, Infektionskrankheiten; Medizinische Universitätsklinik, Tübingen
  • 2Diagnostische und Interventionelle Radiologie, Universitätsklinikum Tübingen, Tübingen
  • 3Innere Medizin IV, Gastroenterologie, Hepatologie, Infektionskrankheiten und Vergiftungen, Universitätsklinikum Heidelberg, Heidelberg
  • 4II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, TU München, München
  • 5Department of Internal Medicine, University Hospital Mainz, Mainz
  • 6Universitätsklinik und Poliklinik für Innere Medizin I, Universitätsklinikum Halle, Halle
  • 7Department of Gastroenterology and Hepatology, University Hospital Essen, Essen
  • 8Innere Klinik (Tumorforschung), Universitätsklinikum Essen, Essen
  • 9I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg
  • 104SC AG, Planegg-Martinsried

Aims: Resminostat (4SC–201), an orally taken pan-HDAC inhibitor, is currently under investigation in various oncological indications. The Phase I/II SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib (S) first-line therapy.

Methods: Pts with advanced HCC (BCLC B, C) are included in a multi-center, open-label, two-arm parallel group trial. Progression under S is confirmed by central review prior to study entry. Arm B investigates resminostat monotherapy, Arm A a combination with S to overcome treatment resistance, including a dose escalation to determine the MTD. Resminostat is administered orally once-daily (“5+9” schedule: 5 treatment days, 9-day rest period) starting from a dose level of 200 (DL 1), to 400 (DL 2) and 600mg (DL 3+4), combined with continuously S at 400 (DL 1–3) or 800mg (DL 4). Primary objective is to determine PFS after 12 weeks. Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers.

Results: To date, 39 pts were included, 17 pts in the dose escalation phase. No DLT occurred in 5 pts treated on DL 4 up to now. Most frequently AE include CTC grade 1–2 GI complaints, including nausea and vomiting, and skin disorders (rash, pruritus, HFSR). CTC Grade 3–4 toxicity consisted mainly of non-hematological events, mostly related to the underlying malignancy. PK analyses of DL 4 revealed consistency with known PK profiles, no PK outlier was detected. Importantly, no trends for accumulation that could rise safety concerns were observed. More than 50% of the patients in the dose escalation phase continued treatment beyond week 12 due to stable disease.

Conclusions: Preliminary clinical data show a favorable drug profile of resminostat in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Data on pharmacokinetics, safety and toxicity will be updated for the meeting.

Clinical Study - Epigenetic Therapeutics - HDAC-Inhibitor - Hepatocellular Carcinoma - Sorafenib - Therapy Resistance