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

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BlankA Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid

Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic

Malignancies

Francis Giles1, Fischer2, Cortes1, Guillermo -Manero1,

Joachim Beck2, Farhad Ravandi1, Masson3, Rae3, Glen Laird3, Sunil

Sharma3, Hagop Kantarjian1, Margaret Dugan3, Maher Albitar4 and Kapil Bhalla5

Authors' Affiliations: 1 Department of Leukemia, University of Texas M.D.

Cancer Center, Houston, Texas; 2 Johannes-Gutenberg-Universität, Mainz,

Germany; 3 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; 4

Quest Diagnostics Nichols Institute, San Capistrano, California; and 5 H.

Lee Moffitt Cancer Center, Tampa, Florida

Correspondence: Requests for reprints: Francis J. Giles, Department of Leukemia,

The University of Texas M.D. Cancer Center, 1400 Holcombe Boulevard,

Box 428, Houston, TX 77030. Phone: 713-792-7305; Fax: 713-794-4297; E-mail:

frankgiles@... .

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.