"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Mechanism Of Action
Denileukin diftitox is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. Ex vivo studies report that after binding to the IL-2 receptor on the cell surface, denileukin diftitox is internalized by receptor-mediated endocytosis. The fusion protein is subsequently cleaved, releasing diphtheria toxin enzymatic and translocation domains from the IL-2 fragment, resulting in the inhibition of protein synthesis and ultimately, cell death.
Pharmacokinetic parameters associated with denileukin diftitox were determined over a range of doses (3 to 31 mcg/kg/day) in patients with lymphoma. Denileukin diftitox was administered as an IV infusion following the schedule used in the clinical trials. Following the first dose, denileukin diftitox displayed 2-compartment behavior with a distribution phase (half-life approximately 2 to 5 minutes) and a terminal phase (half-life approximately 70 to 80 minutes). Systemic exposure was variable but proportional to dose. Mean clearance was approximately 0.6 to 2.0 mL/min/kg and the mean volume of distribution was similar to that of circulating blood (0.06 to 0.09 L/kg). The mean clearance increased approximately 2- to 8-fold from course 1 to course 3 corresponding to a decrease in exposure of approximately 75%. No accumulation was evident between the first and fifth doses. Gender and age have no effect on pharmacokinetics of denileukin diftitox.
Study 1: Placebo Controlled Study in CTCL (Stage Ia to III) Patients
The safety and efficacy of Ontak (denileukin diftitox) were evaluated in a randomized, double-blind, placebo-controlled, 3-arm trial in patients with Stage Ia to III CD25(+) CTCL. Eligible patients were required to have expression of CD25 on ≥ 20% of biopsied malignant cells by immunohistochemistry [seeWARNINGS AND PRECAUTIONS]. Patients were randomized to receive 0, 9 or 18 mcg/kg/day Ontak (denileukin diftitox) via intravenous infusion days 1-5 of each 21-day cycle, for up to 8 cycles. Randomization was stratified by disease stage ( ≤ IIa vs. ≥ IIb). The main efficacy outcome was objective response rate (ORR), using a Weighted Skin Severity Index, in conjunction with assessment of lymph node involvement and percentage of abnormal blood lymphocytes. A total of 144 patients were randomized: 44 patients to placebo, 45 patients to 9 mcg/kg/day Ontak (denileukin diftitox) and 55 patients to 18 mcg/kg/day Ontak (denileukin diftitox) . Randomization for the study was carried out at 1:1:1 for the first 73 patients, 4:1:4 for the next 31 patients, and 1:4:4 for the remaining 40 patients. The median age of patients was 59 years (range 23 to 84 years); 34% were ≥ 65 years. Fifty-five percent were men and 86% were Caucasian. Sixty-seven percent had early stage disease ( ≤ IIa). Patients had received a median of 2 anti-CTCL therapies (range 0 to 6) prior to study entry. Results for objective response rate (ORR) and progression-free survival (PFS) are shown in the table below.
Table 2: Efficacy Results in Study 1
|Efficacy Endpoint||Ontak (denileukin diftitox)
|Ontak (denileukin diftitox)
|Median Response Duration||220 days||277 days||81 days|
|(95% CI)||(0.14, 0.54)||(0.20, 0.86)||--|
|a. Adjusted for disease stage and changes
in randomization ratios
b. Logistic regression model adjusting for disease stage and changes in randomization ratios over the course of the study; comparisons relative to placebo.
c. Cox regression analysis stratified by randomization ratio and adjusted for disease stage; comparisons relative to placebo.
Study 2: Dose Evaluation Study in CTCL (Stage IIb to IVa) Patients
A randomized, double-blind study was conducted to evaluate doses of 9 or 18 mcg/kg/day in 71 patients with recurrent or persistent, Stage Ib to IVa CTCL. Entry to this study required demonstration of CD25 expression on at least 20% of the cells in any relevant tumor tissue sample (skin biopsy) or circulating cells. Tumor biopsies were not evaluated for expression of other IL-2 receptor subunit components (CD122/CD132). Ontak (denileukin diftitox) was administered as an IV infusion daily for 5 days every 3 weeks. Patients received a median of 6 courses of Ontak (denileukin diftitox) therapy (range 1 to 11). The study population had received a median of 5 prior therapies (range 1 to 12) with 63% of patients entering the trial with Stage IIb or more advanced stage disease. The median age of patients was 64 years (range 26 to 91 years); 49% were ≥ 65 years. Fifty-two percent were men and 75% were Caucasian.
Overall, 30% (95% CI: 18-41%) of patients treated with Ontak (denileukin diftitox) experienced an objective tumor response (50% reduction in tumor burden which was sustained for ≥ 6 weeks; Table 3). Seven patients (10%) achieved a complete response and 14 patients (20%) achieved a partial response. The overall median duration of response, measured from first day of response, was 4 months with a median duration for complete response of 9 months and for partial response of 4 months.
Table 3: Efficacy Results in Study 2
|Clinical Response||9 mcg/kg/day||18 mcg/kg/day|
|Complete Response||9% (3/35)||11% (4/36)|
|95% Confidence Interval||(2%, 23%)||(3%, 26%)|
|Partial Response||14% (5/35)||25% (9/36)|
|95% Confidence Interval||(9%, 30%)||(12%, 42%)|
|Overall Response||23% (8/35)||36 (13/36)|
|95% Confidence Interval||(10%, 40%)||(21%, 54%)|
Last reviewed on RxList: 12/4/2008
This monograph has been modified to include the generic and brand name in many instances.
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