"By Kathleen Doheny
WebMD Health News
Reviewed by Arefa Cassoobhoy, MD, MPH
March 10, 2015 -- Drugs known as biologics have grabbed headlines over the years, both for their potential in fighting cancer and other diseases, and f"...
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 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 [see WARNINGS AND PRECAUTIONS]. Patients were randomized to receive 0, 9 or 18 mcg/kg/day Ontak 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 and 55 patients to 18 mcg/kg/day Ontak. 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||Ontak18 mcg/kg/day
|Median Response Duration||220 days||277 days||81 days|
|(95% CI)||(0.14, 0.54)||(0.20, 0.86)||--|
|aAdjusted for disease stage and changes in
bLogistic regression model adjusting for disease stage and changes in randomization ratios over the course of the study; comparisons relative to placebo.
cCox 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 was administered as an IV infusion daily for 5 days every 3 weeks. Patients received a median of 6 courses of Ontak 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 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|
95% Confidence Interval
95% Confidence Interval
95% Confidence Interval
Last reviewed on RxList: 3/11/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Ontak Information
Ontak - User Reviews
Ontak User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options.