83 POSTER A robust and quantitative biomarker assay for SB939, a potent, orally-active HDAC inhibitor

Novotny‐Diermayr, Veronica; Nayagam, Vasantha M.; Hentze, H.; Liang, Aileen; Loh, Yung Kiang; Sausgruber, Nina; Yeo, Pauline; Ethirajulu, Kantharaj; Wood, Jeffrey

doi:10.1016/s1359-6349(08)72015-9

Cited by 2 publications

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“…Based on the preclinical data showing parallel changes in AcH3 in PBMCs and tumour tissue, PBMCs were selected for study in the phase I trial ( Novotny-Diermayr et al , 2008 ; Yong et al , 2009 ).…”

Section: Methodsmentioning

confidence: 99%

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Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours

et al. 2011

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Background:SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours.Methods:Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1–3 and 15–17 every 4 weeks, then on days 1–5 and 15–19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels.Results:In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90 mg and the RPTD was 60 mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6–8.9 h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response.Conclusions:SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60 mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors.

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Section: Methodsmentioning

confidence: 99%

“…PBMCs were extracted from blood, processed to pellet form and stored at −80°C. Levels of AcH3 in PBMCs were determined using a validated western blot technique ( Novotny-Diermayr et al , 2008 ).…”

Section: Methodsmentioning

confidence: 99%

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours

et al. 2011

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“…Changes of this biomarker can be determined via Western blot, fl ow cytometry analysis or immunohistochemical methods. V. Novotny and coworkers produced a sensitive Western blot assay to quantitate histone H3 acetylation on lysine 9 and 14 which was developed to measure target effi cacy of SB939 (29).…”

Section: Histone Acetylationmentioning

confidence: 99%

The development and potential clinical utility of biomarkers for HDAC inhibitors

Shi

2013

Drug Discov Ther

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Drug discovery has always been a complex process including many phases from target validation to clinical development. Data from the Food and Drug Administration (FDA) has estimated that the elimination rate for investigational new drugs entering clinical trials is up to 80%. In recent years, many kinds of biomarkers have been used to predict response in cancer treatment and for evaluation of new drugs. By increasing the understanding of histone deactylase (HDAC) inhibitors cellular mechanism of action, we have elucidated how HDAC inhibitors exert their effect by the use of proper biomarkers. In this paper, we mainly focus on the development and potential clinical utility of HDAC inhibitor biomarkers.

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83 POSTER A robust and quantitative biomarker assay for SB939, a potent, orally-active HDAC inhibitor

Cited by 2 publications

References 0 publications

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours

The development and potential clinical utility of biomarkers for HDAC inhibitors

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