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

Francis Giles, 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

Research output: Contribution to journalArticle

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/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/m 2 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.

Original languageEnglish (US)
Pages (from-to)4628-4635
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number15
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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Hydroxamic Acids
Histone Deacetylase Inhibitors
Hematologic Neoplasms
Acetylation
Histones
Apoptosis
cinnamic acid
panobinostat
Hypokalemia
Myelodysplastic Syndromes
Appetite
Tumor Cell Line
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Thrombocytopenia
Intravenous Administration
Nausea
Area Under Curve
Vomiting
Half-Life

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. / Giles, Francis; Fischer, Thomas; Cortes, Jorge; Garcia-Manero, Guillermo; Beck, Joachim; Ravandi, Farhad; Masson, Eric; Rae, Patricia; Laird, Glen; Sharma, Sunil; Kantarjian, Hagop; Dugan, Margaret; Albitar, Maher; Bhalla, Kapil.

In: Clinical Cancer Research, Vol. 12, No. 15, 01.08.2006, p. 4628-4635.

Research output: Contribution to journalArticle

Giles, F, Fischer, T, Cortes, J, Garcia-Manero, G, Beck, J, Ravandi, F, Masson, E, Rae, P, Laird, G, Sharma, S, Kantarjian, H, Dugan, M, Albitar, M & Bhalla, K 2006, 'A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies', Clinical Cancer Research, vol. 12, no. 15, pp. 4628-4635. https://doi.org/10.1158/1078-0432.CCR-06-0511
Giles, Francis ; Fischer, Thomas ; Cortes, Jorge ; Garcia-Manero, Guillermo ; Beck, Joachim ; Ravandi, Farhad ; Masson, Eric ; Rae, Patricia ; Laird, Glen ; Sharma, Sunil ; Kantarjian, Hagop ; Dugan, Margaret ; Albitar, Maher ; Bhalla, Kapil. / A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 15. pp. 4628-4635.
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T1 - A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies

AU - Giles, Francis

AU - Fischer, Thomas

AU - Cortes, Jorge

AU - Garcia-Manero, Guillermo

AU - Beck, Joachim

AU - Ravandi, Farhad

AU - Masson, Eric

AU - Rae, Patricia

AU - Laird, Glen

AU - Sharma, Sunil

AU - Kantarjian, Hagop

AU - Dugan, Margaret

AU - Albitar, Maher

AU - Bhalla, Kapil

PY - 2006/8/1

Y1 - 2006/8/1

N2 - 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/m 2 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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