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

E Deutsch, ECJ Moyal, V Gregorc, PA Zucali, J Menard, JC Soria, I Kloos, J Hsu, Y Luan, E Liu, R Vezan, T Graef, Sofia Rivera

Research output: Contribution to journalArticle

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 [PR s]), 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. © Deutsch et al.
Original languageEnglish
Pages (from-to)56199-56209
Number of pages11
JournalOncotarget
Volume8
Issue number34
Publication statusPublished - 2017

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Histone Deacetylase Inhibitors
Radiotherapy
Neoplasms
Therapeutics
abexinostat
Lymphopenia
Hypokalemia
Radiation Tolerance
Brain
Combination Drug Therapy
Tumor Cell Line
Thrombocytopenia
Drug Therapy

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A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors. / Deutsch, E; Moyal, ECJ; Gregorc, V; Zucali, PA; Menard, J; Soria, JC; Kloos, I; Hsu, J; Luan, Y; Liu, E; Vezan, R; Graef, T; Rivera, Sofia.

In: Oncotarget, Vol. 8, No. 34, 2017, p. 56199-56209.

Research output: Contribution to journalArticle

Deutsch, E, Moyal, ECJ, Gregorc, V, Zucali, PA, Menard, J, Soria, JC, Kloos, I, Hsu, J, Luan, Y, Liu, E, Vezan, R, Graef, T & Rivera, S 2017, 'A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors', Oncotarget, vol. 8, no. 34, pp. 56199-56209.
Deutsch, E ; Moyal, ECJ ; Gregorc, V ; Zucali, PA ; Menard, J ; Soria, JC ; Kloos, I ; Hsu, J ; Luan, Y ; Liu, E ; Vezan, R ; Graef, T ; Rivera, Sofia. / A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors. In: Oncotarget. 2017 ; Vol. 8, No. 34. pp. 56199-56209.
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