Abstract
This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat. Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.
Highlights
Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agent being developed for several oncologic indications
Clinical activity has been shown in patients with a variety of malignancies, including cutaneous T-cell lymphoma (CTCL), and vorinostat is currently marketed with an indication for the treatment of patients with CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies at a daily dose of 400 mg [3]
Vorinostat is an inhibitor of specific histone deacetylase enzymes and has shown clinical activity in patients with a variety of malignancies, including cutaneous T-cell lymphoma
Summary
Histone deacetylase (HDAC) inhibitors are a new class of antineoplastic agent being developed for several oncologic indications. Vorinostat is a small-molecule inhibitor of class I and II HDAC enzymes [1], which binds directly to the catalytic pocket of HDAC enzymes and is orally bioavailable It has shown preclinical activity in numerous cancer models both in vitro and in vivo [2]. Vorinostat is an inhibitor of specific histone deacetylase enzymes and has shown clinical activity in patients with a variety of malignancies, including cutaneous T-cell lymphoma. Vorinostat is generally well-tolerated and cardiac-associated adverse experiences have not been reported commonly. In nonclinical and clinical studies of romidepsin, there have been reports of cardiac abnormalities including ECG changes with QTc prolongation [4, 5]. In limited ECG sampling, median QTc prolongation was reported as
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