title: Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia.
abstract: Background We determined the safety, pharmacokinetics, pharmacodynamics, and antitumour activity of abexinostat in B-cell lymphoma or chronic lymphocytic leukaemia. Patients and methods Thirty-five patients received oral abexinostat 30, 45, or 60 mg/m(2) bid in a 3 + 3 design in three 21-day schedules: 14 days on treatment in schedule 1 (D1-14); 10 days in schedule 2 (D1-5 and D8-12); and 12 days in schedule 3 (D1-4, D8-11, and D15-18). Safety, tumour response, plasma concentration, and histone H3 acetylation were measured. Results Two dose-limiting toxicities occurred in each schedule (one grade 3 febrile neutropenia; five grade 4 thrombocytopenia) at 60 mg/m(2) bid (maximal tolerated dose). The recommended dose was 45 mg/m(2) bid; schedule 1 was considered optimal. Non-haematological drug-related toxicities included grade 1 or 2 diarrhoea (43%), nausea (23%), and vomiting (11%); haematological toxicities included thrombocytopenia (31% grade 3, and 26% grade 4), which remained manageable and reversible on withdrawal. Of 29 evaluable patients, there were 2 complete and 6 partial responses; median duration of response was 14.6 months (range 3-16.5 months) (1 cycle is equivalent to 0.75 months). There was no evidence for nonlinear pharmacokinetics. There was a correlation between dose and histone acetylation. Conclusion Abexinostat has manageable toxicity and induced some durable complete and partial responses in B-cell lymphoma or chronic lymphocytic leukaemia. Our results suggest most favourable responses in patients with follicular lymphoma, though further research would be needed to confirm this finding.
authors.affiliation: Centre Hospitalier Régional de Lille, Hôpital Claude Huriez, Service des maladies du sang, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA), Université de Lille, Lille, France, franck.morschhauser@chru-lille.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.forename: Louis
authors.initials: L
authors.lastname: Terriou
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bachy
authors.forename: Andrea
authors.initials: A
authors.lastname: Varga
authors.forename: Ioana
authors.initials: I
authors.lastname: Kloos
authors.forename: Hélène
authors.initials: H
authors.lastname: Lelièvre
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Sarry
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006689:Hodgkin Disease / Q000188:drug therapy; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat