A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies.
OBJECTIVE
LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle.


METHODS
Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m(2)): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed.


RESULTS
Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m(2) and one at 11.5 mg/m(2). QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19(+); P = 0.02) and blasts (CD34(+); P = 0.04). The increase in H2B acetylation was highest in CD19(+) and CD34(+) cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34(+) and CD19(+) cells significantly increased on therapy as did apoptosis in CD14(+) cells. Area under the curve increased proportionally with dose with a terminal half-life of approximately 11 hours.


CONCLUSIONS
Intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m(2) with consistent transient antileukemic and biological effects.
Giles
Francis
F
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA. frankgiles@aol.com
Fischer
Thomas
T
Cortes
Jorge
J
Garcia-Manero
Guillermo
G
Beck
Joachim
J
Ravandi
Farhad
F
Masson
Eric
E
Rae
Patricia
P
Laird
Glen
G
Sharma
Sunil
S
Kantarjian
Hagop
H
Dugan
Margaret
M
Albitar
Maher
M
Bhalla
Kapil
K
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005500:Follow-Up Studies; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D007211:Indoles; D007275:Injections, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D000077767:Panobinostat; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011237:Predictive Value of Tests; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D002934:Cinnamates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat