title: Phase 1 dose-escalation study of oral abexinostat for the treatment of patients with relapsed/refractory higher-risk myelodysplastic syndromes, acute myeloid leukemia, or acute lymphoblastic leukemia.
abstract: Histone deacetylase (HDAC) inhibitor abexinostat is under investigation for the treatment of various cancers. Epigenetic changes including aberrant HDAC activity are associated with cancers, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). In this phase 1 dose-escalation study, 17 patients with relapsed/refractory higher-risk MDS, AML, or ALL received oral abexinostat (60, 80 [starting dose], 100, or 120 mg) twice daily (bid) on Days 1-14 of 21-day cycles. The most common treatment-related grade ≥3 adverse events were thrombocytopenia (29%) and neutropenia (24%), none of which led to discontinuation. Maximum-tolerated dose was not reached. Of 12 evaluable patients, best response was stable disease in 1 patient. This study was closed due to limited clinical benefit. Future development of oral abexinostat 100 mg bid in patients with MDS, AML, or ALL should focus on combination regimens. ISRCTN registry: 99680465.
authors.affiliation: a Department of Hematology , Institut Paoli Calmettes, SIRIC-Marseille , Marseille , France.|b Aix-Marseille University , Marseille , France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: c Internal Medicine Department, Section of Hematology , Yale Cancer Center at Yale University , New Haven , CT , USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.affiliation: d Department of Medical Pharmacology , CIC 1436, Université Toulouse Hospital, Inserm , Toulouse , France.
authors.forename: Claire
authors.initials: C
authors.lastname: Thalamas
authors.affiliation: a Department of Hematology , Institut Paoli Calmettes, SIRIC-Marseille , Marseille , France.
authors.forename: Aude
authors.initials: A
authors.lastname: Charbonnier
authors.affiliation: a Department of Hematology , Institut Paoli Calmettes, SIRIC-Marseille , Marseille , France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Rey
authors.affiliation: e Department of Oncology Research and Development , Institut de Recherches Internationales Servier , Suresnes , France.
authors.forename: Ioana
authors.initials: I
authors.lastname: Kloos
authors.affiliation: f Biometrics, Pharmacyclics , LLC, an AbbVie Company , Sunnyvale , CA , USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Liu
authors.affiliation: f Biometrics, Pharmacyclics , LLC, an AbbVie Company , Sunnyvale , CA , USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luan
authors.affiliation: g Department of Clinical Science, Pharmacyclics , LLC, an AbbVie Company , Sunnyvale , CA , USA.
authors.forename: Remus
authors.initials: R
authors.lastname: Vezan
authors.affiliation: g Department of Clinical Science, Pharmacyclics , LLC, an AbbVie Company , Sunnyvale , CA , USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.affiliation: h Service d'Hématologie , Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole , Toulouse , France.|i Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294-CNRS , Toulouse , France.
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
mesh_terms: D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy*; D012008:Recurrence; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat
keywords: Abexinostat; HDAC inhibitors; acute lymphoid leukemia; acute myeloid leukemia; myelodysplastic syndromes