Reference Detail

Ref Type

Journal Article

PMID

(23647373)

Authors

Ossenkoppele GJ, Lowenberg B, Zachee P, Vey N, Breems D, Van de Loosdrecht AA, Davidson AH, Wells G, Needham L, Bawden L, Toal M, Hooftman L, Debnam PM

Title

A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of haematology	162	2	2013 Jul	191-201	Br J Haematol

URL

Abstract Text

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).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Tefinostat	Tefinostat	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Tefinostat		CHR-2845\|CHR 2845\|CHR2845	HDAC Inhibitor 45	Tefinostat (CHR-2845) is a monocyte/macrophage targeted HDAC inhibitor, which may result in decreased proliferation of hCE1-expressing hematological tumor cells (PMID: 23647373).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References