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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Leukemia, Adult T-Cell

Intervention / Treatment
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* Biological: Denileukin diftitox (Ontak)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have serum antibodies directed to human T-lymphotropic virus type 1 (HTLV-I). All patients must have a histologically confirmed diagnosis of adult T-cell leukemia/lymphoma and more than 10% of the malignant cells must express cluster of differentiation 25 (CD25). All stages of Tac-expressing adult T cell leukemia except smoldering are eligible: patients with chronic, lymphomatous or acute adult T-cell leukemia (ATL) are eligible. (See appendix 2 for characteristics of patients with the various stages of ATL) Patients must have measurable disease. All patients with greater than 10% abnormal (i.e. TAC homogenous strongly expressing) peripheral blood mononuclear cells (PBMC) in the peripheral blood will be deemed to have measurable disease. The patient must have a granulocyte count of at least 1000/mm^3 and a platelet count of greater than or equal to 50,000/mm^3. Patients must have a creatinine of less than 2.0 mg/dl. Omission of cytotoxic chemotherapy for ATL for 3 weeks prior to entry into the trial is required. However, patients receiving corticosteroids will be eligible. Patients must have a life expectancy of greater than 2 months. Eligible patients must be greater than or equal to 18 years old. There is no upper age limit. Patients must have serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) value less than or equal to 2.5 times the upper limit of normal and bilirubin less than or equal to 3.0/dl. If a liver function test is judged to be elevated due to the underlying ATL, this parameter will be considered an unevaluable parameter for toxicity determinations. Patients must have a serum albumin greater than or equal to 2.5 g/dl Patients must be able to understand and sign an Informed Consent form. All patients must use adequate contraception during participation in this trial and for three months after completing therapy. EXCLUSION CRITERIA: Patients with symptomatic leukemic meningitis will be excluded. However, patients that have both ATL and another HTLV-I-associated disease, tropical spastic paraparesis (TSP), will be included. Pregnant and nursing patients are not eligible for the study. Human immunodeficiency virus (HIV) positive patients are excluded from the study. Denileukin diftitox may produce a different pattern of toxicities in immunocompromised individuals. Patients with Smoldering ATL are excluded. Patients with serious intercurrent illnesses, past history of a myocardial infarction within 6 months or severe coronary artery disease Patients who previously received Denileukin diftitox are ineligible.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denileukin Diftitox in ATL<br>Denileukin Diftitox in adult T-cell leukemia (ATL) Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks. | Biological: Denileukin diftitox (Ontak)<br>* Patients will be treated with Denileukin Diftitox 9 mcg/kg/d intravenously for 5 days every 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate is based on the number of patients who achieve either a complete response (CR) or partial response (PR) to therapy. Complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease related symptoms if present before therapy and normalization of those biochemical abnormalities (for example LDH) definitely assignable to the lymphoma. Partial response is reduction by >=50% of leukemia cell count or >=50% reduction is the size of all measurable lesions, and no increase in size of any measurable or evaluable lesion or appearance of new lesion. | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-Serious Adverse Events | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 72 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Denileukin Diftitox (Ontak), Recombinant Immunotoxin, Human T-Cell Lymphotropic Virus (HTLV1), CD25 Positive, IL-2R, ATL, Ontak, Adult T-Cell Leukemia, Lymphoproliferative Disorders