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Oncotarget. 2016 Dec 24;8(34):56199-56209. doi: 10.18632/oncotarget.14147. eCollection 2017 Aug 22.

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

Author information

1
Department of Radiation Oncology, Gustave-Roussy Cancer Campus, Villejuif, France.
2
INSERM 1030 Molecular Radiotherapy, Villejuif, France.
3
Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, 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 (Département d'Innovations Thérapeutiques et Essais Précoces), 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.

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.

KEYWORDS:

abexinostat; brain lesions; histone deacetylase inhibitor; radiotherapy; solid tumors

Conflict of interest statement

CONFLICTS OF INTEREST ED, consulting or advisory role for Roche, research funding from Servier, Roche, AstraZeneca, travel accommodations from Merck, Roche; ECJM, consulting or advisory role for Merck; VG, consulting or advisory role for and travel accommodations from Pfizer, Novartis, Eli Lilly, Roche, AstraZeneca, Boehringer Ingelheim; PAZ, no relevant financial disclosures; JM, no relevant financial disclosures; JCS, no relevant financial disclosures; IK, patients, royalties, or other intellectual property for Servier; JH, employment with Pharmacyclics and Astellas Pharma (Agensys), stock or other ownership for AbbVie; YL, employment with Pharmacyclics, stock or other ownership for AbbVie; EL, employment for Pharmacyclics, Theorem Clinical Research, stock or other ownership for AbbVie; RV, employment for Pharmacyclics, stock or other ownership for AbbVie; TG, employment and patents, royalties, or other intellectual property for Pharmacyclics, stock or other ownership for AbbVie; SR, travel accommodations from Novartis.

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