Michael Bitzer1, Marius Horger2, Edoardo G Giannini3, Tom M Ganten4, Marcus A Wörns5, Jens T Siveke6, Matthias M Dollinger7, Guido Gerken8, Max E Scheulen9, Henning Wege10, Vittorina Zagonel11, Umberto Cillo12, Franco Trevisani13, Armando Santoro14, Vincenzo Montesarchio15, Nisar P Malek16, Julia Holzapfel17, Thomas Herz17, Astrid S Ammendola17, Stefano Pegoraro17, Bernhard Hauns17, Anna Mais17, Ulrich M Lauer16, Stefan W Henning17, Bernd Hentsch17. 1. Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany. Electronic address: michael.bitzer@uni-tuebingen.de. 2. Department of Diagnostic & Interventional Radiology, Eberhard Karls University, Tuebingen, Germany. 3. Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy. 4. Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany. 5. First Department of Medicine, Johannes Gutenberg-University, Mainz, Germany. 6. Second Department of Internal Medicine, Technical University, Munich, Germany. 7. Internal Medicine I, University Ulm, Ulm, Germany. 8. Center for Internal Medicine, University Clinic, Essen, Germany. 9. Department of Medical Oncology, West German Cancer Center, Essen, Germany. 10. University Hospital Hamburg-Eppendorf, Hamburg, Germany. 11. Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy. 12. Hepatobiliary Surgery and Liver Transplant Unit, Azienda Università di Padova, Padova, Italy. 13. University of Bologna, Bologna, Italy. 14. Department of Oncology, Humanitas Cancer Center, Rozzano, Italy. 15. UO Oncologia Ospedale Cotugno Napoli, Napoli, Italy. 16. Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany. 17. 4SC AG, Planegg-Martinsried, Germany.
Abstract
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 600mg resminostat plus 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 deacetylase inhibition and highest increase in H4-acetylation matched Tmax 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 (12weeks, 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 4.1months for resminostat and 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 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.
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 600mg resminostat plus 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 deacetylase inhibition and highest increase in H4-acetylation matched Tmax 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 (12weeks, 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 4.1months for resminostat and 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 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.
Authors: T Nakatsuka; K Tateishi; Y Kudo; K Yamamoto; H Nakagawa; H Fujiwara; R Takahashi; K Miyabayashi; Y Asaoka; Y Tanaka; H Ijichi; Y Hirata; M Otsuka; M Kato; J Sakai; M Tachibana; H Aburatani; Y Shinkai; K Koike Journal: Oncogene Date: 2017-07-10 Impact factor: 9.867