Phase 1 study of the oral histone deacetylase ...
Document type :
Article dans une revue scientifique
PMID :
Permalink :
Title :
Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia
Author(s) :
Morschhauser, Franck [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Terriou, Louis [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Coiffier, Bertrand [Auteur]
Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL]
Bachy, Emmanuel [Auteur]
Centre Hospitalier Lyon Sud [CHU - HCL] [CHLS]
Varga, Andrea [Auteur]
Institut Gustave Roussy [IGR]
Kloos, Ioana [Auteur]
Institut de Recherches SERVIER [IRS]
Lelievre, Helene [Auteur]
Institut de Recherches Internationales Servier [Suresnes] [IRIS]
Sarry, Anne-Laure [Auteur]
Institut de Recherches Internationales Servier [Suresnes] [IRIS]
Depil, Stephane [Auteur]
Institut de Recherches SERVIER [IRS]
Ribrag, Vincent [Auteur]
Institut Gustave Roussy [IGR]

Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Terriou, Louis [Auteur]

Lille Inflammation Research International Center - U 995 [LIRIC]
Coiffier, Bertrand [Auteur]
Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL]
Bachy, Emmanuel [Auteur]
Centre Hospitalier Lyon Sud [CHU - HCL] [CHLS]
Varga, Andrea [Auteur]
Institut Gustave Roussy [IGR]
Kloos, Ioana [Auteur]
Institut de Recherches SERVIER [IRS]
Lelievre, Helene [Auteur]
Institut de Recherches Internationales Servier [Suresnes] [IRIS]
Sarry, Anne-Laure [Auteur]
Institut de Recherches Internationales Servier [Suresnes] [IRIS]
Depil, Stephane [Auteur]
Institut de Recherches SERVIER [IRS]
Ribrag, Vincent [Auteur]
Institut Gustave Roussy [IGR]
Journal title :
Investigational new drugs
Abbreviated title :
Invest. New Drugs
Volume number :
33
Pages :
423-431
Publication date :
2015-01-21
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CHU Lille
Inserm
CHU Lille
Inserm
Collections :
Research team(s) :
Innovation/évaluation des médicaments injectables
Submission date :
2019-02-26T17:07:43Z
2021-06-14T09:07:17Z
2021-06-14T09:07:17Z