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Regulatory Issues: FDA

FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Key Words. Vorinostat • Histone deacetylase inhibitor • HDAC • Cutaneous T-cell lymphoma • CTCL

Correspondence: Bhupinder S. Mann, M.D., U.S. Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2103, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1411; Fax: 301-796-9845; e-mail: bhupinder.mann{at}fda.hhs.gov

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza®; Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had Sézary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%–41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%–61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.