Histone deacetylase (HDAC) inhibitors are emerging as a promising new class of targeted oncolytic drugs. They act by inducing apoptotic cell death in cancer cells but not in normal cells, which are comparatively resistant to the apoptosis-inducing effects of these agents. As such, they are associated with low toxicity and good tolerability, and hold potential in the treatment of both hematologic and solid tumor malignancies.

The HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) is currently undergoing clinical development at Merck & Co. for the treatment of various cancers. Preclinical and clinical trial results were featured at the AACR and ASCO meetings, as highlighted in DailyDrugNews.com and below.

A phase I study involving 23 patients with advanced cancer examined the safety, tolerability and pharmacokinetics of the agent (400 mg q.d. for 28 days) in fasted and fed states. Vorinostat was well tolerated. Adverse events related to treatment were thrombocytopenia, increased serum creatinine, anorexia/weight loss, nausea/vomiting and fatigue. Twenty-three and fourteen patients were evaluable for day 1, single-dose and day 28, multidose pharmacokinetics, respectively. The rate of absorption of the agent was reduced in the presence of a standard high-fat meal. In the fed states, most patients had a delay of a minimum of 15 minutes before levels of vorinostat could be detected in serum and the Tmax was slightly delayed. Mean apparent terminal t1/2 values were short and similar for both single- and multiple dosing and for the fed and fasted states (Rubin, E.H. et al. 97th Annu Meet Am Assoc Cancer Res: Abst 2907).

Vorinostat (400 mg o.d.) was administered to 74 patients with advanced, refractory cutaneous T-cell lymphoma in a phase IIb study. The objective response rate was 30%, and safety was acceptable (Olsen, E. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 7500).

Vorinostat was combined with carboplatin and paclitaxel in a phase I study in patients with advanced solid tumors. The recommended dose for further evaluation of the combination was vorinostat 300 mg/day plus carboplatin 6 AUC and paclitaxel 175 mg/m2. Vorinostat pharmacokinetics were not affected by the other agents, and 4 partial response and 2 examples of stable disease were seen (Ramalingam, S. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 2077).

Vorinostat doses of 100, 200 and 300 mg were combined with FOLFOX in 9 patients with advanced colorectal cancer included in a phase I study. No dose-limiting toxicities were seen and accrual to the highest dose level is ongoing. Evidence of activity includes 3 patients with stable disease and downregulation of thymidylate synthase with the lowest dose (Fakih, M.G. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 3592).

The FDA has accepted for review Merck & Co.'s NDA for vorinostat (Zolinza™) for the treatment of advanced cutaneous T-cell lymphoma (CTCL) (orphen drug designation). The filing has been granted priority review and the company expects FDA action on the NDA by early October 2006. If approved, vorinostat would potentially be the first in the HDAC inhibitor class of anticancer therapies.