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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 2 Johannes-Gutenberg-Universität, Mainz, Germany; 3 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; 4 Quest Diagnostics Nichols Institute, San Juan Capistrano, California; and 5 H. Lee Moffitt Cancer Center, Tampa, Florida
Requests for reprints: Francis J. Giles, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Box 428, Houston, TX 77030. Phone: 713-792-7305; Fax: 713-794-4297; E-mail: frankgiles{at}aol.com.
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/m2): 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/m2 and one at 11.5 mg/m2. 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 <11.5 mg/m2 with consistent transient antileukemic and biological effects.
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