A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of the histone deacetylase (HDAC) inhibitor PXD101 in patients (pts) with advanced solid tumours

Steele, N.; Vidal, Laura; Plumb, JA; Attard, Gerhardt; Rasmussen, Åse Krogh; Buhl-Jensen, P.; Brown, R. Malcolm; Blagden, Sarah P.; Evans, JA; Bono, J. de

doi:10.1200/jco.2005.23.16_suppl.3035

Cited by 18 publications

(14 citation statements)

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“…Electrocardiogram effects described as nonspecific T-wave or ST segment abnormalities have been reported with the use of depsipeptide, SAHA and LAQ824 (13, 46 -48). Supraventricular tachycardia, the doselimiting event reported from the NCI phase I trial with depsipeptide, was reported as a dose-limiting toxicity in a phase I trial of PXD101 and was reported in patients treated on a phase I trial of MS-275 when given daily (13,49,50). In patients treated with LBH589, a hydroxamic acid, QTc prolongation of >500 milliseconds was noted in 5 of 12 (42%) patients treated at higher dose levels (51).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma

Piekarz

Frye

Wright

et al. 2006

Clinical Cancer Research

230

166

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Purpose: The histone deacetylase inhibitor depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, STsegment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. Results: Cardiac studies from 282 cycles and 736 doses of depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for z6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate^corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. Conclusion: The data obtained in this study show that the administration of depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate^corrected QT interval prolongation remains under study.

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Section: Discussionmentioning

confidence: 99%

Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma

Piekarz

Frye

Wright

et al. 2006

Clinical Cancer Research

230

166

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“…Vorinostat has also been shown to have synergistic or additive effects with a wide range of chemotherapeutics in preclinical studies, and clinical combination studies are underway. Additional examples of hydroxamic acid HDACi include LAQ824 and LBH589, PXD-101, and CRA-24781 [143][144][145][146][147][148].…”

Section: Classes Of Hdaci's and Their Anticancer Propertiesmentioning

confidence: 99%

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

et al. 2007

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Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.

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“…Only one LC/MS/MS method was mentioned for PXD101 quantification in mice and canine plasma. 12 In a recent Phase I trial, Steele et al 13 reported PXD101 plasma concentrations varying from .10 ng/mL to 100 mg/mL. Accordingly, a sensitive HPLC method using solid-phase extraction, with ultraviolet (UV) detection, was developed for the determination of PXD101 in human plasma and validated in this laboratory.…”

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confidence: 98%

“…12 In a Phase I study, the toxicity profile was acceptable up to a dose of 1000 mg/m, 2 at which no grade 4 toxicity was observed. 13 PXD101 is currently in Phase II clinical trials for the treatment of multiple myeloma, both as a single agent and in combination with dexamethasone, and as a single-agent treatment for cutaneous and other T-cell lymphomas. PXD101 is also being evaluated in a Phase Ib trial with 5-fluorouracil for the treatment of solid tumors, including colorectal cancer, and with paclitaxel and carboplatin for the treatment of advanced solid tumors such as ovarian cancer.…”

mentioning

confidence: 99%

“…PXD101 is also being evaluated in a Phase Ib trial with 5-fluorouracil for the treatment of solid tumors, including colorectal cancer, and with paclitaxel and carboplatin for the treatment of advanced solid tumors such as ovarian cancer. [13][14][15] A phase I/II study of PXD101 for the treatment of hepatocellular carcinoma in patients is underway by the Cancer Therapeutic Research Group (CTRG; members from Hong Kong, Korea, Australia and Singapore). To support the clinical study, a sensitive and reliable high-performance liquid chromatographic (HPLC) assay for quantification of PXD101 in plasma had to be developed.…”

mentioning

confidence: 99%

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A Simple and Sensitive High-Performance Liquid Chromatographic Method for Quantification of PXD101, a Histone Deacetylase Inhibitor in Human Plasma

Goh

Khoo

Park³

et al. 2007

Therapeutic Drug Monitoring

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PXD101, a new histone deacetylase inhibitor, is currently undergoing phase I/II clinical trials as an anticancer drug. This study describes a simple and sensitive high-performance liquid chromatography ultraviolet method developed for the quantification of PXD101 in human plasma samples to support such trials. Following solid phase extraction at room temperature, the analytes were separated on a 5 mum C18 150 x 2.1 mm column using gradient elution (mobile phase of acetonitrile and 25 mM NaH2PO4, pH 2.8) at a flow rate of 0.5 mL/min and ultraviolet detection at 268 nm. Oxamflatin was used as an internal standard. PXD101 and the internal standard were eluted at about 7.9 min and 13.6 min, respectively. The lower limit of quantification of PXD101 in plasma was 10 ng/mL. The calibration curves for concentrations in the range of 10 to 2,000 ng/mL gave excellent linearity (r = 0.999). The coefficients of variation for intraday and interday assays were all less than 10%. The accuracy of all concentration determinations ranged from 98.0% to 102.0%. There were no problems with PXD101 stability following freeze-thawing, short-term exposure to room temperature, postextraction stability up to 24 hours, and sample storage at -70 degrees C for 3 months. The reported method, with dilution integrity of up to 50 fold, has the requisite sensitivity and is suitable for pharmacokinetic studies of PXD101.

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A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study of the histone deacetylase (HDAC) inhibitor PXD101 in patients (pts) with advanced solid tumours

Cited by 18 publications

References 0 publications

Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma

Cardiac Studies in Patients Treated with Depsipeptide, FK228, in a Phase II Trial for T-Cell Lymphoma

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

A Simple and Sensitive High-Performance Liquid Chromatographic Method for Quantification of PXD101, a Histone Deacetylase Inhibitor in Human Plasma

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