Phase II Study of the Efficacy and Toxicity of Ontak(Registered Trademark) (Denileukin Diftitox) in the Therapy of Adult T-Cell Leukemia

Leukemia, Adult T-Cell

Denileukin Diftitox (Ontak), Recombinant Immunotoxin, Human T-Cell Lymphotropic Virus (HTLV1), CD25 Positive, IL-2R, ATL, Ontak, Adult T-Cell Leukemia, Lymphoproliferative Disorders

Adult T-cell leukemia (ATL) is and aggressive characterized by the presence of cluster of differentiation 4 (CD4)/cluster of differentiation 25 (CD25)-expressing T cells (interleukin-2 \[IL-2\]R expressing) in the peripheral blood and in lymphoid and other tissues. Denileukin diftitox (Ontak(Registered Trademark)) is a genetically engineered fusion protein that targets IL-2-expressing malignancies. Denileukin diftitox interacts with the IL-2R on the cell surface, is internalized via endocytosis, and inhibits cellular protein synthesis, resulting in cell death within hours to days. The objectives of this study are to determine the clinical response to Denileukin diftitox of patients with adult T-cell leukemia (ATL) and the safety of Denileukin diftitox in those patients. Eligible participants must be 18 years of age or older with chronic, lymphomatous and acute forms of ATL, and must be infected with human T-cell lymphotropic virus type I (HTLV1). Patients will be treated with 9 mcg/kg/d of Denileukin diftitox intravenously for 5 days every 2 weeks. Tumor response will be evaluated after two cycles of treatment. Stable or responding patients will continue treatment for a total of 12 months, with evaluations every four cycles of treatment. Patients will be treated for two cycles beyond a complete remission. The trial uses an optimal two-stage design targeting for a true response proportion of more than 30 percent. Nine patients will be treated initially, with expansion to 29 patients if a response is seen in 1 of the initial 9 patients treated. Treatment will be discontinued if a patient experiences serious side effects. A potential benefit is that a patient may undergo partial or complete remission. The research may not directly benefit participants, but the results may aid in the treatment of others.

Background: Adult T-Cell Leukemia is a lymphoproliferative disorder characterized by the presence of CD4/CD25 expressing T cells (IL-2R expressing) in the peripheral blood, in lymphoid and other tissues. Denileukin diftitox is a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin (DT) and the full length sequence of interleukin-2 (IL-2) that targets IL-2 expressing malignancies. Denileukin diftitox interacts with the IL-2 R on the cell surface, is internalized via endocytosis, and inhibits cellular protein synthesis resulting in cell death within hours to days. Objective: Determine the clinical response to Denileukin diftitox (Ontak) of patients with adult T-cell leukemia (ATL). Define the safety of Denileukin diftitox in patients who have ATL. Eligibility: Patients with chronic, lymphomatous and acute forms of ATL. Patients must be human T-cell lymphotropic virus type I (HTLV1) positive. Design: Patients will be treated with 9mcg/kg/d of Denileukin diftitox for five days, on an every two week schedule. Tumor response will be evaluated after two cycles of treatment. Stable or responding patients will continue treatment with evaluations every four cycles of treatment. Patients will be treated for two cycles beyond a complete remission. The trial uses an optimal 2 stage design targeting for a true response proportion greater than 30%. Nine patients will be treated initially with expansion to 29 patients if a response is seen in one of the initial nine patients treated. If no response is seen at the 9 mcg/kg/d dose an additional 9 patients will be treated at a dose of 18 mcg/kg/d with expansion to 29 patients at this dose level if a response is seen. A stopping rule for excessive toxicity will be incorporated.

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