A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors

Steele, N.; Plumb, Jane A.; Vidal, Laura; Tjørnelund, Jette; Knoblauch, Poul; Rasmussen, Annie; Ooi, Chean Eng; Buhl-Jensen, P.; Brown, Robert E.; Evans, T.R. Jeffry; Bono, Johann S. de

doi:10.1158/1078-0432.ccr-07-1786

Cited by 230 publications

(202 citation statements)

References 12 publications

(5 reference statements)

Supporting

Mentioning

198

Contrasting

Order By: Relevance

“…In this trial, belinostat was well-tolerated, exhibited dose-dependent pharmacodynamic (PD) effects, and had promising anti-tumour activity. The maximum tolerated dose of belinostat administered intravenously in this dose and schedule was 1000mg/m 2 /day [6]. marked in the first few hours following intravenous drug administration.…”

Section: Introductionmentioning

confidence: 94%

“…This study was conducted as an extension to the phase 1 trial of intravenous belinostat which has previously been reported [6]. Eligible patients were those with histologic or cytologic confirmed advanced malignancy, refractory to standard therapy, or for whom no standard therapy existed.…”

Section: Patient Eligibilitymentioning

confidence: 99%

“…Two milliliter aliquots of plasma were stored at -70°C until analysis. The concentration of belinostat in plasma was analysed by liquid chromatography with tandem mass spectrometry detection as previously described [6]. PK calculations were performed using a non-compartmental method (WinNonLin version 5. were collected in lithium heparin vacutainer tubes, placed on ice and processed immediately using a modification of the method described by Yoshida et al [7] and as previously described [6].…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

“…The concentration of belinostat in plasma was analysed by liquid chromatography with tandem mass spectrometry detection as previously described [6]. PK calculations were performed using a non-compartmental method (WinNonLin version 5. were collected in lithium heparin vacutainer tubes, placed on ice and processed immediately using a modification of the method described by Yoshida et al [7] and as previously described [6]. Densitometry was carried out on the resulting Western blots and the results were expressed relative to a control sample (histones extracted from A2780 ovarian cancer cell line treated for 1 hour with belinostat 0.2µM).…”

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

“…Inhibition of tumour growth by belinostat is associated with a marked increase in the level of acetylation of histone proteins [5]. We have previously reported the results of a phase I trial of belinostat administered as a 30-minute intravenous infusion on days 1-5 of a 21-day cycle [6]. In this trial, belinostat was well-tolerated, exhibited dose-dependent pharmacodynamic (PD) effects, and had promising anti-tumour activity.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele

Plumb

Vidal

et al. 2010

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

PurposeThe primary objective of this sub-study, undertaken as an extension to the previously reported phase I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary PD studies were also performed to enable comparison of the biologic effects of the oral and intravenous formulations. Patients and MethodsOral belinostat was administered in a range of doses and schedules (once, twice, or thrice daily), on either day 1 or days 1 -5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase I trial of intravenous belinostat.Serial blood samples were collected for pharmacokinetic and pharmacodynamic (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. ResultsA total mean daily AUC of 2767 1453 ng hr/ml (8.7 4.6 M hr) resulted from a dose of 1000 mg/m 2 once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid) however a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half life (T½) of a single dose of 1000 mg/m 2 was 1.5 hr ( 0.3 hr) and peak levels were reached in an average of 1.9hrs ( 0.3 hr). The half life was found to be independent of dose, but a trend towards increasing half life following multiple dosing was observed. Histone H4 4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. ConclusionsHigh doses of oral belinostat, up to 1000 mg/m 2 bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat.

show abstract

Section: Introductionmentioning

confidence: 94%

Section: Patient Eligibilitymentioning

confidence: 99%

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Section: Pharmacokinetic Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele

Plumb

Vidal

et al. 2010

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

Stroke Therapy

Nantermet

Shalen

Shankar

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

show abstract

Belinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma

et al. 2017

View full text Add to dashboard Cite

There have been advances in personalized therapy directed by molecular profiles in lung adenocarcinoma, but not in lung squamous cell carcinoma (SCC). The lack of actionable driver oncogenes in SCC has restricted the use of small‐molecule inhibitors. Here, we show that SCC cell lines displayed differential sensitivities to belinostat, a pan‐histone deacetylase inhibitor. Phosphoproteomic analysis of belinostat‐treated SCC cells revealed significant downregulation of the MAPK pathway, along with the induction of apoptosis. In cisplatin‐resistant cells that demonstrated aberrant MAPK activation, combined treatment with belinostat significantly inhibited cisplatin‐induced ERK phosphorylation and exhibited strong synergistic cytotoxicity. Furthermore, belinostat transcriptionally upregulated the F‐box proteins FBXO3 and FBXW10, which directly targeted son of sevenless (SOS), an upstream regulator of the MAPK pathway, for proteasome‐mediated degradation. Supporting this, suppression of SOS/ERK pathway by belinostat could be abrogated by inhibiting proteasomal activity either with bortezomib or with siRNA knockdown of FBXO3/FBXW10. Taken together, these preclinical data offer a novel understanding of the epigenetic mechanism by which belinostat exerts its cytotoxicity and supports the combination with cisplatin in clinical settings for chemorefractory SCC tumors.

show abstract

A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors

Cited by 230 publications

References 12 publications

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Stroke Therapy

Belinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma

Contact Info

Product

Resources

About