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A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia
Author(s) -
Kadia Tapan M.,
Yang Hui,
Ferrajoli Alessandra,
Maddipotti Sirisha,
Schroeder Claudia,
Madden Timothy L.,
Holleran Julianne L.,
Egorin Merrill J.,
Ravandi Farhad,
Thomas Deborah A.,
Newsome Willie,
SanchezGonzalez Blanca,
Zwiebel James A.,
EspinozaDelgado Igor,
Kantarjian Hagop M.,
GarciaManero Guillermo
Publication year - 2010
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2010.08211.x
Subject(s) - vorinostat , idarubicin , medicine , pharmacology , histone deacetylase inhibitor , histone deacetylase , oncology , mucositis , cancer research , chemotherapy , biology , cytarabine , histone , biochemistry , gene
Summary 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.