Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia

Invest New Drugs. 2015 Apr;33(2):423-31. doi: 10.1007/s10637-015-0206-x. Epub 2015 Jan 21.

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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

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

Substances

  • Benzofurans
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • abexinostat