Oncotarget

Research Papers:

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 _, Elizabeth Cohen-Jonathan Moyal, Vanesa Gregorc, Paolo Andrea Zucali, Jean Menard, Jean-Charles Soria, Ioana Kloos, Jeff Hsu, Ying Luan, Emily Liu, Remus Vezan, Thorsten Graef and Sofia Rivera

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Oncotarget. 2017; 8:56199-56209. https://doi.org/10.18632/oncotarget.14147

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Abstract

Eric Deutsch1,2,3, Elizabeth Cohen-Jonathan Moyal4, Vanesa Gregorc5, Paolo Andrea Zucali6, Jean Menard7, Jean-Charles Soria8, Ioana Kloos9, Jeff Hsu10, Ying Luan10, Emily Liu10, Remus Vezan10, Thorsten Graef10, Sofia Rivera1,2,3

1Department of Radiation Oncology, Gustave-Roussy Cancer Campus, Villejuif, France

2INSERM 1030 Molecular Radiotherapy, Villejuif, France

3Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

4Department of Radiation Oncology, Institut Claudius Regaud, Toulouse, France

5Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale San Raffaele, Milan, Italy

6Department of Medical Oncology and Haematology, Humanitas Cancer Center, IRCCS, Rozzano, Italy

7Department of Radiation Oncology, Hopital Saint-Louis, Paris, France

8DITEP (Département d’Innovations Thérapeutiques et Essais Précoces), Gustave Roussy Cancer Campus, Villejuif, France

9Institut de Recherches Internationales Servier, Clinical Pharmacokinetics, Suresnes, France

10Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA

Correspondence to:

Eric Deutsch, email: [email protected]

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/m2 (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.


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