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

• Published in: International journal of clinical oncology Vol. 18; no. 1; pp. 87 - 95
• Main Authors: Doi, Toshihiko, Hamaguchi, Tetsuya, Shirao, Kuniaki, Chin, Kensho, Hatake, Kiyohiko, Noguchi, Kazuo, Otsuki, Tetsuya, Mehta, Anish, Ohtsu, Atsushi
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01.02.2013; Springer Nature B.V
• Subjects: Aged; Cancer Research; Chemotherapy; Clinical outcomes; Clinical trials; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions - chemically induced; Female; Gastric cancer; Gastroenterology; Gastrointestinal Neoplasms - blood; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - pathology; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - adverse effects; Histone Deacetylase Inhibitors - blood; Histone Deacetylase Inhibitors - pharmacokinetics; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - adverse effects; Hydroxamic Acids - blood; Hydroxamic Acids - pharmacokinetics; Inhibitor drugs; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Staging; Oncology; Original Article; Surgical Oncology; Histone deacetylase inhibitor (HDACi); Gastrointestinal cancer; Vorinostat; Suberoylanilide hydroxamic acid (SAHA)
• ISSN: 1341-9625; 1437-7772
• DOI: 10.1007/s10147-011-0348-6

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 [AUC 0–∞ ] of 7.75 ± 2.79 μM h on Day 1 post-dose) compared with 300 mg bid (AUC 0–∞ 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.