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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

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Summary

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/m2 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/m2 bid (maximal tolerated dose). The recommended dose was 45 mg/m2 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.

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Disclosures

F.M., E.B., and A.V.: no relevant conflicts of interest to disclose. L.T.: honoraria from Servier, Amgen, and GSK; consultancy for Pfizer. B.C. consultancy, honoraria, and research funding for Celgene; honoraria from Servier. I.K., H.L., A-L.S. and S.D.: employees of Servier. V.R.: membership of board of directors or advisory committees for Servier, AstraZeneca, and Takeda; research funding from Servier, Bayer, and Sanofi.

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All authors participated in the study design, the interpretation of the results, the development and writing of the manuscript, and the decision to submit for publication. The sponsor was responsible for data management and the final data analyses.

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Correspondence to Franck Morschhauser.

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Table 1S

Plasma pharmacokinetic parameters for abexinostat. Cmax, maximum concentration achieved for sampling time up to 4 hours tmax, time in hours taken to reach maximum concentration. AUC24, area under the curve for sampling time up to 24 hours t½z, terminal elimination half-life. NA: not applicable. (DOC 28 kb)

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Morschhauser, F., Terriou, L., Coiffier, B. et al. 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 33, 423–431 (2015). https://doi.org/10.1007/s10637-015-0206-x

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  • DOI: https://doi.org/10.1007/s10637-015-0206-x

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