A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies - PubMed (original) (raw)

Clinical Trial

. 2006 Aug 1;12(15):4628-35.

doi: 10.1158/1078-0432.CCR-06-0511.

Thomas Fischer, Jorge Cortes, Guillermo Garcia-Manero, Joachim Beck, Farhad Ravandi, Eric Masson, Patricia Rae, Glen Laird, Sunil Sharma, Hagop Kantarjian, Margaret Dugan, Maher Albitar, Kapil Bhalla

Affiliations

Clinical Trial

A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies

Francis Giles et al. Clin Cancer Res. 2006.

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.

Experimental design: 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.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources