Abstract
Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2.5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting.
Publication types
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Clinical Trial, Phase I
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Randomized Controlled Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Acute Disease
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Adult
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Aged
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Aged, 80 and over
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / blood
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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DNA Topoisomerases, Type II / biosynthesis
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DNA Topoisomerases, Type II / genetics
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Dose-Response Relationship, Drug
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Female
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Histones / metabolism
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Humans
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Hydroxamic Acids / administration & dosage
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Hydroxamic Acids / adverse effects
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Hydroxamic Acids / blood
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Idarubicin / administration & dosage
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Idarubicin / adverse effects
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Idarubicin / blood
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Leukemia / blood
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Leukemia / drug therapy*
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Leukemia, Myeloid, Acute / blood
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Leukemia, Myeloid, Acute / drug therapy
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Male
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Middle Aged
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Poly-ADP-Ribose Binding Proteins
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RNA, Messenger / genetics
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Recurrence
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Vorinostat
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Young Adult
Substances
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Antigens, Neoplasm
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Histones
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Hydroxamic Acids
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Poly-ADP-Ribose Binding Proteins
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RNA, Messenger
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Vorinostat
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DNA Topoisomerases, Type II
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TOP2A protein, human
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Idarubicin