FDA Okays Zolinza for CTCL Skin Lesions

November 1, 2006

The Food and Drug Administration has approvedZolinza (vorinostat, Merck) as a once-a-day oral treatment of the skinmanifestations of cutaneous T-cell lymphoma(CTCL) in patients whose diseasehas persisted, progressed, or recurredduring or following two systemic therapies.

ROCKVILLE, Maryland--TheFood and Drug Administration has approvedZolinza (vorinostat, Merck) as aonce-a-day oral treatment of the skinmanifestations of cutaneous T-cell lymphoma(CTCL) in patients whose diseasehas persisted, progressed, or recurredduring or following two systemic therapies.The agency granted Zolinza marketingapproval as part of its OrphanDrug program and on the basis of datafrom two open-label clinical studies inpatients with refractory CTCL. Treatedpatients had an objective response rate ofnearly 30%.

The drug is taken daily with food as asingle 400 mg oral dose. If the patient isintolerant to therapy, the dose may bereduced to 300 mg orally once daily withfood. The dose may be further reducedto 300 mg once daily with food for 5consecutive days each week.

Zolinza is the first of a new class ofdrugs, the histone deacetylase (HDAC)inhibitors, to gain FDA approval. Basedon in vitro studies, Zolinza inhibits theenzymatic activity of HDAC1, HDAC2,HDAC3, and HDAC6 at nanomolar concentrations. In some cancer cells, excessamounts of HDAC prevent the activationof genes that control normal cellactivity. Zolinza is believed to decreaseHDAC activity, which allows for the activationof genes that may help to slow orstop the growth of cancer cells. In a pressrelease, Merck noted that the exactmechanism of the anticancer effect ofZolinza has not been fully characterized.

Pivotal Study
Merck submitted as its pivotal studyan open-label, single-arm, nonrandomized,multicenter trial of 74 patientstreated with 400 mg Zolinza once daily.The primary endpoint was the responserate of the skin disease. Secondary endpointswere response duration, time toprogression, and time to objective response.Patients had received a median of three therapies prior to enrollment(range, 1 to 12).

Of the 74 patients, 22 (29.7%) had anobjective response to Zolinza, as did 18(29.5%) of the 61 patients with stage IIBor higher CTCL. Median times to response,respectively, were 55 and 56 days(range, 28 to 171 days). Median durationwas not reached because most responsescontinued at the time of analysis, but itwas estimated to exceed 6 months in boththe overall population and patients withstage IIB or higher disease. When end ofresponse was defined as a 50% increasein a scale that assesses skin lesions, theestimated median response duration was168 days and the median time to tumorprogression was 202 days.

Dosing Study
In the open-label, nonrandomizeddosing study, 33 patients were dividedinto three cohorts receiving one of threeZolinza doses: 400 mg daily, 300 mg twicedaily 3 days per week, or 300 mg twicedaily for 14 days followed by a 7-day rest.Overall, 8 (24.2%) of the patients had an objective response and 7 (25%) of the 28with stage IIB or higher disease responded.The overall response rates were30.8%, 9.1%, and 33.3% in Cohorts 1, 2,and 3, respectively. The 300 mg twicedaily regimen had higher toxicity withno additional clinical benefit over the400 mg once daily regimen.

Among the 8 responders, median timeto response was 83.5 days (range, 25 to153 days); duration of response lasted amedian of 106 days (range, 66 to 136days); and median time to progressionwas 211.5 days (range, 94 to 255 days).

Safety Data
FDA evaluated safety data from 86 ofthe 107 patients enrolled in the two trialswho had received Zolinza at a dose of400 mg once daily. The most commonserious adverse events were pulmonaryembolism, dehydration, deep vein thrombosis,and anemia. The most commonother adverse events were gastrointestinalsymptoms, including diarrhea, nausea,anorexia, vomiting, and constipation;fatigue; chills; and taste disorders.

Physicians should be alert to the signsand symptoms of pulmonary embolismand deep vein thrombosis, particularlyin patients with a prior history of thromboembolicevents. Treatment with Zolinzacan cause dose-related thrombocytopeniaand anemia. If platelet countsand/or hemoglobin are reduced duringtreatment with Zolinza, the dose shouldbe modified or therapy discontinued.Gastrointestinal disturbances may requirethe use of antiemetic and antidiarrhealmedications.

Preexisting nausea, vomiting, and diarrheashould be adequately controlledbefore beginning therapy. Fluids and electrolytesshould be replaced to preventdehydration, and patients should be instructedto drink at least 2 L/d of fluids.

Although Zolinza's fetal effects duringpregnancy have not been examinedin controlled trials, preclinical animalstudies have indicated that use of the drugat that time can cause fetal harm.