FDA Approval for Vorinostat
Brand name(s): Zolinza™
- Approved for cutaneous manifestations of cutaneous T-cell lymphoma
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On October 6, 2006, the U.S. Food and Drug Administration granted approval to vorinostat (Zolinza™, Merck & Co., Inc.), 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 major trial supporting approval was a single-arm open-label trial conducted at 18 centers in the U.S. and Canada that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). All patients received vorinostat at a dose of 400 mg once daily which could be reduced for toxicity to 300 mg orally daily or 300 mg orally five days a week.
The median age of patients was 61 years. Sixty-one patients (82 percent) had stage IIB or higher CTCL and 30 patients (41 percent) had Sézary syndrome. The median duration of protocol treatment was 118 days.
Skin disease response was assessed using a Severity Weighted Assessment Tool (SWAT). This tool calculated an overall score based on the percentages of the total body surface area involved with patch, plaque, or tumor lesions, with weighting of each by factors of one, two, and four, respectively.
Response was defined as a 50 percent or greater decrease in the SWAT score and disease progression as a 50 percent increase in the score from the nadir. In this study, 30 percent experienced responses; the estimated median response duration was 168 days and the median time to tumor progression was 202 days (see the protocol summary).
An additional single center study enrolled 33 patients with similar baseline and demographic features as in the major trial. Thirteen of the 33 were treated at the same dose of 400 mg/day. The responses in these 13 patients were similar to those observed in the major efficacy trial.
Adverse events (AEs) were reported irrespective of the relation to the study drug. In the major efficacy trial, the most common clinical AEs of any grade were diarrhea (51 percent), fatigue (51 percent), nausea (43 percent), and anorexia (27 percent). Grade 3, 4, or 5 clinical AEs included fatigue (7 percent), and pulmonary embolism (5.4 percent).
Chemistry laboratory abnormalities observed were hypercholesterolemia (66 percent), hypertriglyceridemia (66 percent), hyperglycemia (64 percent), and increased creatinine (45 percent). Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.
Hematologic laboratory abnormalities were anemia (54 percent), thrombocytopenia (42 percent), low white blood cell (WBC) count (24 percent), and low neutrophil count (14 percent). Most of these were of grades 1 or 2 in severity.
For safe use of vorinostat, patients must be kept well hydrated and blood counts and chemistry tests should be obtained every two weeks during the first two months of therapy and monthly thereafter. Adjustments in diet and drugs may be necessary in patients with diabetes.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.