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Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

From the Duke University Medical Center, Durham, NC; University of Texas Anderson Cancer Center, Houston, and University of Texas Health Sciences Center at San Antonio, San Antonio, TX; Hollings Cancer Center, Charleston, SC; Stanford University, Stanford, University of California Los Angeles, Los Angeles, and City of Hope, Duarte, CA; Washington University, St Louis, MO; Allegheny University, Philadelphia, and University of Pittsburgh, Pittsburgh, PA; University Hospital of Cleveland, Cleveland, OH; Indiana University, Indianapolis, IN; Yale University, New Haven, CT; Roswell Park Cancer Institute, Buffalo, and Columbia Presbyterian, New York, NY; University of Michigan, Ann Arbor, and Henry Ford Health System, Detroit, MI; Northwestern University Medical School, Chicago, IL; Boston University Medical Center, Boston, and Seragen, Inc, Hopkinton, MA; University of Colorado, Denver, CO; and Vanderbilt University, Nashville, TN.

Address reprint requests to Elise A. Olsen, MD, Duke University Medical Center, Box 3294, Durham, NC 27710; email olsen001{at}mc.duke.edu

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB₃₈₉IL-2, Ontak [Ligand Phar-maceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.

PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on 20% of lymphocytes were assigned to one of two dose levels (9 or 18 µg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti–interleukin-2 and serum concentrations of denileukin diftitox were also measured.

RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 µg/kg/d was similar, and there was no evidence of cumulative toxicity.

CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

None of the authors have equity interests in Seragen with the exception of P.B. and J.N.. Seragen, Inc is a wholly owned subsidiary of Ligand Pharmaceuticals Inc, San Diego, CA. Seragen holds the license for Ontak.

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