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: Franck Morschhauser, Louis Terriou, Bertrand Coiffier, Emmanuel Bachy, Andrea Varga, Ioana Kloos, Hélène Lelièvre, Anne-Laure Sarry, Stéphane Depil, Vincent Ribrag
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 2 Pg. 423-31 (Apr 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25600050 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Benzofurans
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• abexinostat

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols
• Benzofurans (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Hodgkin Disease (drug therapy)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Lymphoma, Non-Hodgkin (drug therapy)
• Lymphoproliferative Disorders (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged