Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma:in vitroand phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition

Reinhard Dummer*a, Marc Beyer*b, Kenneth Hymesc, Mirjam T. Eppingd, Rene Bernardsd, Matthias Steinhoffb, Wolfram Sterryb, Helmut Kerle, Karl Heathf, Janet D. Ahernf, James S. Hardwickf, Jose Garcia-Vargasf, Katrin Baumanna, Syed Rizvif, Stanley R. Frankelf, Sean J. Whittakerg & Chalid Assafbha University Hospital Zürich, Switzerlandb Charitè-Universitätsmedizin, Berlin, Germanyc New York University Clinical Cancer Center, NY, USAd The Netherlands Cancer Institute, Amsterdam, The Netherlandse Medical University of Graz, Austriaf Columbia University, New York, NY, USAg King's College London, UKh Helios Klinikum, Krefeld, GermanyCorrespondence: Dr. Reinhard Dummer, University Hospital Zürich, Department of Dermatology, Gloriastrasse 31, CH-8091, Zürich, Switzerland. Tel: + 41-1-255-1111. Fax: + 41-1-255-9032. E-mail: reinhard.dummer@usz.chDr. Marc Beyer, Charité Universitätsmedizin Berlin, Department of Dermatology and Allergy, Skin Cancer Center Charité, Charitéplatz 1, 10117, Berlin, Germany. Tel: + 49-30-450618369. Fax: + 49-30-450518949. E-mail: marc.beyer@charite.deAbstractThe retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.