title: A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies.
abstract: Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte-targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).
authors: Department of Haematology, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Gert J
authors: GJ
authors: Ossenkoppele
authors: Bob
authors: B
authors: Lowenberg
authors: Pierre
authors: P
authors: Zachee
authors: Norbert
authors: N
authors: Vey
authors: Dimitri
authors: D
authors: Breems
authors: Arjan A
authors: AA
authors: Van de Loosdrecht
authors: Alan H
authors: AH
authors: Davidson
authors: Graham
authors: G
authors: Wells
authors: Lindsey
authors: L
authors: Needham
authors: Lindsay
authors: L
authors: Bawden
authors: Martin
authors: M
authors: Toal
authors: Leon
authors: L
authors: Hooftman
authors: Phillip M
authors: PM
authors: Debnam
mesh_terms: D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*
chemical_list: D000813:Anilides; C586099:CHR 2845; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids
keywords: clinical trial; haemato-oncology; histone deacetylase inhibitor; macrophage; monocyte