A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors

// Eric Deutsch 1, 2, 3 , Elizabeth Cohen-Jonathan Moyal 4 , Vanesa Gregorc 5 , Paolo Andrea Zucali 6 , Jean Menard 7 , Jean-Charles Soria 8 , Ioana Kloos 9 , Jeff Hsu 10 , Ying Luan 10 , Emily Liu 10 , Remus Vezan 10 , Thorsten Graef 10 , Sofia Rivera 1, 2, 3 1 Department of Radiation Oncology, Gustave-Roussy Cancer Campus, Villejuif, France 2 INSERM 1030 Molecular Radiotherapy, Villejuif, France 3 Faculte de Medecine, Universite Paris-Sud, Universite Paris-Saclay, Le Kremlin-Bicetre, France 4 Department of Radiation Oncology, Institut Claudius Regaud, Toulouse, France 5 Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy 6 Department of Medical Oncology and Haematology, Humanitas Cancer Center, IRCCS, Rozzano, Italy 7 Department of Radiation Oncology, Hopital Saint-Louis, Paris, France 8 DITEP (Departement d’Innovations Therapeutiques et Essais Precoces), Gustave Roussy Cancer Campus, Villejuif, France 9 Institut de Recherches Internationales Servier, Clinical Pharmacokinetics, Suresnes, France 10 Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA Correspondence to: Eric Deutsch, email: eric.deutsch@gustaveroussy.fr Keywords: abexinostat, histone deacetylase inhibitor, radiotherapy, solid tumors, brain lesions Received: July 28, 2016 Accepted: November 14, 2016 Published: December 24, 2016 ABSTRACT Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m 2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.