A Phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor, in patients with advanced solid tumors
Mené sur 92 patients atteints d'un cancer de stade avancé, cet essai de phase I évalue la toxicité et l'efficacité du quisinostat, un inhibiteur d'histones désacétylases
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).
Experimental Design: In this first-in-human, phase I study quisinostat was administered orally, once-daily in 3-weekly cycles to patients with advanced malignancies, using a 2-stage accelerated titration design. Three intermittent schedules were subsequently explored: 4 days on/3 days off; every Mon, Wed, Fri (MWF); and every Mon, Thurs (M-Th). Toxicity, pharmacokinetics, pharmacodynamics and clinical efficacy were evaluated at each schedule.
Results: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy and vomiting. DLTs observed were predominantly cardiovascular, including non-sustained ventricular tachycardia, ST/T-wave abnormalities and other tachyarhythmias. Non-cardiac DLTs were fatigue and abnormal liver function tests. Quisinostat Cmax and AUC increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting 5 months was seen in one patient with melanoma. Stable disease was seen in 8 patients (duration 4-10.5 months).
Conclusions: The adverse event profile of quisinostat was comparable to that of other HDACi. Intermittent schedules were better tolerated than continuous. Based on tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule.