FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma

On October 6, 2006, the U. S. Food and Drug Administration granted regular approval to vorinostat ( Zolinza (R); 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 Sezary 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.