A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies

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 ∼11 hours. Conclusion: Intravenous administration of LBH589 was well tolerated at doses