title: Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.
authors.affiliation: Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany. Electronic address: michael.bitzer@uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
authors.affiliation: Department of Diagnostic & Interventional Radiology, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Horger
authors.affiliation: Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy.
authors.forename: Edoardo G
authors.initials: EG
authors.lastname: Giannini
authors.affiliation: Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
authors.affiliation: First Department of Medicine, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Wörns
authors.affiliation: Second Department of Internal Medicine, Technical University, Munich, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Internal Medicine I, University Ulm, Ulm, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Dollinger
authors.affiliation: Center for Internal Medicine, University Clinic, Essen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Department of Medical Oncology, West German Cancer Center, Essen, Germany.
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.affiliation: University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Wege
authors.affiliation: Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy.
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
authors.affiliation: Hepatobiliary Surgery and Liver Transplant Unit, Azienda Università di Padova, Padova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Trevisani
authors.affiliation: Department of Oncology, Humanitas Cancer Center, Rozzano, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: UO Oncologia Ospedale Cotugno Napoli, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Montesarchio
authors.affiliation: Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Holzapfel
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Herz
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Astrid S
authors.initials: AS
authors.lastname: Ammendola
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pegoraro
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hauns
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Mais
authors.affiliation: Department of Internal Medicine I, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Henning
authors.affiliation: 4SC AG, Planegg-Martinsried, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hentsch
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D006801:Humans; D006877:Hydroxamic Acids; D008113:Liver Neoplasms; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D000077157:Sorafenib; D013449:Sulfonamides
chemical_list: D006877:Hydroxamic Acids; D010671:Phenylurea Compounds; D013449:Sulfonamides; C550599:resminostat; D009536:Niacinamide; D000077157:Sorafenib
keywords: Cancer epigenetics; Drug resistance; Epigenetic treatment; Histone deacetylase inhibitor; Zinc finger protein 64