General: Denileukin diftitox is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. The human IL-2 receptor exists in three forms, low (CD25), intermediate (CD122/CD132) and high (CD25/CD122/CD132) affinity. The high affinity form of this receptor is usually found only on activated T lymphocytes, activated B lymphocytes and activated macrophages. Malignant cells expressing one or more of the subunits of the IL-2 receptor are found in certain leukemias and lymphomas including cutaneous T-cell lymphoma (CTCL)¹. Ex vivo studies suggest that denileukin diftitox interacts with the high affinity IL-2 receptor on the cell surface and inhibits cellular protein synthesis, resulting in cell death within hours.

The biodistribution and excretion of radiolabeled denileukin diftitox were evaluated over 48 hours in rats. The liver and kidneys were the primary sites of distribution and accumulation of radiolabeled material outside of the vasculature. Denileukin diftitox was metabolized by proteolytic degradation. Excreted material was less than 25% of the total injected dose and consisted of low molecular weight breakdown products.

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. Clearance was approximately 1.5 to 2.0 mL/min/kg and the volume of distribution was similar to that of circulating blood (0.06 to 0.08 L/kg). No accumulation was evident between the first and fifth doses. Development of antibodies to denileukin diftitox has been shown to significantly impact clearance rates (see PRECAUTIONS, Immunogenicity). Gender, age, and race were introduced into a multivariate analysis with various pharmacokinetic parameters. The limited available data revealed no statistical relationships between these variables.

Clinical Studies

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. 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 1). 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. In a Phase I/II dose-escalation study, 35 patients with Stage Ia to IVb CTCL were treated. ONTAK was administered as an IV infusion at doses ranging from 3 to 31 mcg/kg/day, daily for 5 days every 3 weeks. The overall response rate in patients with CTCL who expressed CD25 was 38% (12 of 32 patients); the complete response rate was 16% and the partial response rate was 22%. There were no responses in 21 patients with Hodgkin's disease.

Table 1: Response in the Phase III Double-Blind Study Patients with CTCL

REFERENCES

1. Nakase K, Kita K, Nasu K, Ueda T, Tanaka I, Shirakawa S and Tsudo M. Differential expression of interleukin-2 receptor (α and β chain) in mature lymphoid neoplasms. Amer. J. Hematol. 1994; 46: 179-183.

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