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A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia.

Author(s): Kadia TM, Yang H, Ferrajoli A, Maddipotti S, Schroeder C, Madden TL, Holleran JL, Egorin MJ, Ravandi F, Thomas DA, Newsome W, Sanchez-Gonzalez B, Zwiebel JA, Espinoza-Delgado I, Kantarjian HM, Garcia-Manero G

Affiliation(s): Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

Publication date & source: 2010-07, Br J Haematol., 150(1):72-82. Epub 2010 Apr 29.

Publication type: Clinical Trial, Phase I; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

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.

Page last updated: 2010-10-05

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