A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies.
Clin Cancer Res
; 12(15): 4628-35, 2006 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-16899611
ABSTRACT
PURPOSE:
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. EXPERIMENTALDESIGN:
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.CONCLUSION:
Intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m(2) with consistent transient antileukemic and biological effects.
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Bases de datos:
MEDLINE
Asunto principal:
Síndromes Mielodisplásicos
/
Leucemia Mieloide
/
Inhibidores Enzimáticos
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
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Inhibidores de Histona Desacetilasas
/
Ácidos Hidroxámicos
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Aged80
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos