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Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia
- Source :
- Investigational new drugs, Investigational new drugs, 2015, Investigational new drugs, 33, pp.423-431. ⟨10.1007/s10637-015-0206-x⟩
- Publication Year :
- 2015
- Publisher :
- HAL CCSD, 2015.
-
Abstract
- International audience; 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.
- Subjects :
- Adult
Male
medicine.medical_specialty
Maximum Tolerated Dose
Nausea
[SDV]Life Sciences [q-bio]
Follicular lymphoma
Abexinostat
Pharmacology
Hydroxamic Acids
Gastroenterology
Drug Administration Schedule
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Pharmacology (medical)
Histone H3 acetylation
030304 developmental biology
Aged
Benzofurans
Aged, 80 and over
0303 health sciences
Dose-Response Relationship, Drug
business.industry
Lymphoma, Non-Hodgkin
Middle Aged
medicine.disease
Hodgkin Disease
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoproliferative Disorders
3. Good health
Lymphoma
Histone Deacetylase Inhibitors
Oncology
chemistry
030220 oncology & carcinogenesis
Pharmacodynamics
Vomiting
Female
medicine.symptom
business
Febrile neutropenia
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Investigational new drugs, Investigational new drugs, 2015, Investigational new drugs, 33, pp.423-431. ⟨10.1007/s10637-015-0206-x⟩
- Accession number :
- edsair.doi.dedup.....25d8fd154cb3a9c3e39f4ed9eb327d79