Efficacy and safety of denileukin diftitox (Dd) in a phase III, double-blind, placebo-controlled study of CD25+ patients with cutaneous T-cell lymphoma (CTCL)

Abstract

8026 Background: ONTAK®(Dd), a genetically engineered fusion protein combines the enzymatically active domain of diphtheria toxin with the sequence of interleukin-2 (IL-2), designed to target IL-2 receptor expressing malignancies. Dd received FDA accelerated approval for the treatment of CTCL in patients with the CD25 component of the IL-2 receptor. Methods: The confirmatory placebo- controlled L4389–11 phase III trial evaluated 9 and 18μg/kg/d Dd in 144 patients with CD25(+) CTCL. Patients (=3 prior treatments, stages Ia - III) received Dd or placebo IV for up to 8 cycles, consisting of Dd once daily for 5 days every 3 weeks. Tumor burden in skin, blood and lymph nodes and a physician's global (PGA) were assessed relative to baseline and before every treatment cycle beginning with cycle 2. Confirmation of tumor response required two more consecutive cycles (3 observations). Investigator assessments were ratified by an independent Drug Evaluation Review Committee. Results: Initial analysis of activity and benefit shown below. Both Dd treatment arms were greatly superior to placebo in a dose dependent fashion. Population demographics were the same across treatment arms (median age 59 years, 55% male). Randomization was stratified by disease status at baseline, 67% were = stage IIa, 33% were =stage IIb. Response between stage groups within each arm did not differ significantly. Many responses were confirmed after 5 or more cycles. AEs were similar to those in previous Dd studies. The only significantly different Grade 3/4 adverse event was nausea (2% in Placebo and 15% in 18μg/kg/d). No differences in serious adverse events among treatment arms were observed. The frequency of AEs and SAEs markedly decrease after the first two cycles of treatment. Conclusions: This is the largest randomized, placebo controlled trial conducted in CTCL, providing clear evidence for efficacy and clinical benefit for Dd. No significant financial relationships to disclose. [Table: see text]