Abstract
Background
Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors.
Methods
Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response.
Results
The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for >8 weeks, with the maximum duration of 245 days. Mean drug exposure (±SD) was generally higher with 400 mg qd (area under the curve [AUC0–∞] of 7.75 ± 2.79 μM h on Day 1 post-dose) compared with 300 mg bid (AUC0–∞ of 3.94 ± 1.56 μM h on Day 1 post-dose).
Conclusions
Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.
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Conflict of interest
Noguchi and Otsuki are employees of MSD K.K., a subsidiary of Merck & Co., Inc., and may own stock or stock options in the company. Mehta is an employee of Merck Sharp & Dohme, Corp., and may own stock or stock options in the company. The other authors report no conflicts of interest.
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Doi, T., Hamaguchi, T., Shirao, K. et al. Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial. Int J Clin Oncol 18, 87–95 (2013). https://doi.org/10.1007/s10147-011-0348-6
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DOI: https://doi.org/10.1007/s10147-011-0348-6