A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors.
Schlüsselwörter
Abstrakt
OBJECTIVE
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.
