A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia.
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.
Kadia
Tapan M
TM
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Hui
H
Ferrajoli
Alessandra
A
Maddipotti
Sirisha
S
Schroeder
Claudia
C
Madden
Timothy L
TL
Holleran
Julianne L
JL
Egorin
Merrill J
MJ
Ravandi
Farhad
F
Thomas
Deborah A
DA
Newsome
Willie
W
Sanchez-Gonzalez
Blanca
B
Zwiebel
James A
JA
Espinoza-Delgado
Igor
I
Kantarjian
Hagop M
HM
Garcia-Manero
Guillermo
G
D000107:Acetylation; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D015255:Idarubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D007938:Leukemia / Q000097:blood / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D000077337:Vorinostat; D055815:Young Adult
D000951:Antigens, Neoplasm; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006657:Histones; D006877:Hydroxamic Acids; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D000077337:Vorinostat; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D015255:Idarubicin
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