On October 15, 2008, the U. S. Food and Drug Administration converted the approval of denileukin diftitox (Ontak^®, Eisai Medical Research) solution for intravenous use for the treatment of persistent or recurrent CD-25 positive cutaneous T-cell lymphoma from accelerated approval to regular approval following confirmation of an improvement in progression-free survival (PFS) and overall response rate (ORR). Denileukin diftitox was originally approved in 1999 under the accelerated approval program for this indication based on durable, objective responses in an open-label study comparing two different doses. A further description of the FDA accelerated approval regulations is at http://www.fda.gov/cder/guidance/5645fnl.htm.

Efficacy was demonstrated in a placebo-controlled multinational, dose-ranging study enrolling 144 patients with CD-25 positive stages Ia-III cutaneous T-cell lymphoma. Patients had three or fewer prior therapies and were randomized to receive either an IV infusion of denileukin diftitox at 18 or 9 mcg/kg days 1-5 of a 21-day cycle (maximum 8 cycles) or placebo (saline).

The three study arms were balanced for baseline demographic characteristics. Patients were required to have CD-25 expression in tumor specimens on central laboratory testing. The median age was 59 years; 34% were age 65 years or older. Sixty-five percent had less advanced (≤ IIa) disease; the median number of prior therapies was two.

Efficacy data were based on determination of ORR, supported by response duration and PFS determined by an independent endpoint review committee. ORR on the 18 mcg/kg dose arm was 46%, 37% on the 9 mcg/kg arm, and 16% in the placebo arm with median response durations of 220, 277 and 81 days, respectively. Significant improvements of PFS at both doses of denileukin diftitox was noted (hazard ratio 0.27 comparing 18 mcg/kg vs. placebo, p=0.0002; hazard ratio 0.42 comparing the 9 mcg/kg vs. placebo, p=0.02).

Treatment-emergent adverse events occurring at an incidence of greater than or equal to 20% (18 mcg/kg group) and more frequently than in the placebo arm were fever, nausea, rigors, fatigue, vomiting, headache, peripheral edema, diarrhea, anorexia, rash, and myalgia. Serious adverse events in patients receiving denileukin diftitox include infusion reactions, capillary leak syndrome, and loss of visual acuity, including loss of color vision. Laboratory abnormalities reported included hypoalbuminemia and hepatic transaminitis.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.fda.gov/cder/foi/label/2008/103767s5094lbl.pdf.