RIPTION
Ontak (denileukin diftitox), is a recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His and the sequences for human interleukin-2 (IL-2; Ala1-Thr133). It is produced in an E.coli expression system and has a molecular weight of 58kD. Neomycin is used in the fermentation process but is undetectable in the final product. Ontak is supplied in single use vials as a sterile, frozen solution intended for intravenous (IV) administration. Each 2mL vial of Ontak contains 300mcg of recombinant denileukin diftitox in a sterile solution of citric acid (20mM), EDTA (0.05mM) and polysorbate20 (<1%) in Water for Injection, USP. The solution has a pH range of 6.9 to 7.2.
12 CLINICAL PHARMACOLOGY
12.1 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. Exvivo 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.
12.3 Pharmacokinetics
Pharmacokinetic parameters associated with denileukin diftitox were determined over a range of doses (3 to 31mcg/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 5minutes) and a terminal phase (half-life approximately 70 to 80minutes). Systemic exposure was variable but proportional to dose. Mean clearance was approximately 0.6 to 2.0mL/min/kg and the mean volume of distribution was similar to that of circulating blood (0.06 to 0.09L/kg). The mean clearance increased approximately 2- to 8-fold from course1 to course3 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There have been no studies to assess the carcinogenic potential of denileukin diftitox. Denileukin diftitox showed no evidence of mutagenicity in the Ames test and the chromosomal aberration assay. There have been no studies to assess the effect of denileukin diftitox on fertility.
14 CLINICAL STUDIES
14.1 Study 1: Placebo Controlled Study in CTCL (StageIa to III) Patients
The safety and efficacy of Ontak were eva luated in a randomized, double-blind, placebo-controlled, 3-arm trial in patients with StageIa 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 (5.4)]. Patients were randomized to receive 0, 9 or 18mcg/kg/day Ontak via intravenous infusion days1-5 of each 21-day cycle, for up to 8cycles. 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 lymphoc
