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Ontak

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Ontak

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

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.

Clinical Studies

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)
18 mcg/kg/day
(N=55)
Ontak (denileukin diftitox)
9 mcg/kg/day
(N=45)
Placebo
(N=44)
ORR %a 46% 37% 15%
  p-valueb p=0.002 p=0.03 --
Median Response Duration 220 days 277 days 81 days
PFSc      
  Hazard ratio 0.27 0.42  
  (95% CI) (0.14, 0.54) (0.20, 0.86) --
  p-value p=0.0002 p=0.02  
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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