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Ref Type | Journal Article | ||||||||||||
PMID | (18245542) | ||||||||||||
Authors | Steele NL, Plumb JA, Vidal L, Tjørnelund J, Knoblauch P, Rasmussen A, Ooi CE, Buhl-Jensen P, Brown R, Evans TR, DeBono JS | ||||||||||||
Title | A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. | ||||||||||||
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Abstract Text | To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors.Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels.Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. I.v. belinostat displayed linear pharmacokinetics with respect to C(max) and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for > or =4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease.I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity. |
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