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FDA Approval for Denileukin Diftitox

Brand name: Ontak®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

On October 15, 2008, the Food and Drug Administration (FDA) converted the approval of denileukin diftitox (Ontak®, made by 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 cutaneous T-cell lymphoma based on durable objective responses in an open-label study comparing two different doses. 

Efficacy was demonstrated in a placebo-controlled multinational dose-ranging study that enrolled 144 patients with CD-25 positive stages Ia-III cutaneous T-cell lymphoma. Patients who had three or fewer prior therapies were randomly assigned to receive an IV infusion of either denileukin diftitox at 0.018 mg/kg  or 0.009 mg/kg on 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 percent were age 65 years or older.  Sixty-five percent had less advanced (≤ stage IIa) disease; the median number of prior therapies was two.

Efficacy data were based on determination of ORR, supported by response duration, and PFS as determined by an independent endpoint review committee.  ORR for patients receiving the 0.018 mg/kg dose was 46 percent and median response duration of 220 days.  ORR for patients on receiving the 0.009 mg/kg dose was 37 percent and median response duration of 277 days. Patients receiving the saline placebo had an ORR of 16 percent and median response duration of 81 days.           

Significant improvements of PFS at both doses of denileukin diftitox was noted (hazard ratio 0.27 comparing 0.018 mg/kg vs. placebo, p=0.0002; hazard ratio 0.42 comparing the 0.009 mg/kg vs. placebo, p=0.02).

Treatment-emergent adverse events that occurred in at least 20 percent  of patients in the 0.018 mg/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.

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 "Learn How Drugs and Devices Get Approved.") 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.

  • Updated: July 2, 2013