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

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 1to 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 (1patient), 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

The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)

“…Here we demonstrate that LBH589 alone, in nanomolar range which is far from toxic range in humans [28], is able to reduce the viability of ER-positive MCF-7…”

The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of multiple myeloma in the 5T2MM and 5T33MM murine models

“…[25][26][27][28] Phase I clinical trials have also shown that some HDACi, such as suberoylanilide hydroxamic acid (SAHA), panobinostat and belinostat, are able to reduce tumor burden in patients with MM. [29][30][31] However, it is unclear, besides the direct in vitro effects on MM cells, how the BM microenvironment is affected by these HDACi, and more specifically how crucial processes like induction of bone disease and angiogenesis are affected.…”

Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

“…It showed poor oral bioavailability in rodents (F=6% in rats) and moderate F in dogs (33-50%) (Konsoula et al, 2009). Like SAHA, Panabinostat was first tried as an intravenous formulation in the phase 1 clinical trials (Giles et al, 2006). In that study, LBH589 showed dose proportional increase in C max and AUC between 4.8 and 14 mg/m 2 , with the terminal half-life ranging between 8-16 h. The V ss and CL were not reported.…”