Protocol Number: 00-C-0030

Title:

A Phase I/II Study of the Efficacy and Toxicity of Humanized Anti-Tac (Zenapax™ (Trademark)) in the Therapy of Tac-Expressing Adult T-Cell Leukemia

Number:

00-C-0030

Summary:

The purpose of the study is to determine: (1) the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac (daclizumab), (Zenapax® (Registered Trademark)) in patients with ATL; (2) to define the dose of Zenapax® (Registered Trademark) required to saturate IL-2R alpha in patients with ATL; (3) determine the clinical response to humanized (Hu) anti-Tac (Zenapax® (Registered Trademark) of patients with Tac-expressing adult T-cell leukemia; and (4) determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu)-anti-Tac in patients who have ATL. This study represents an extension of Metabolism Branch NCI protocols utilizing modifications of the original murine anti-Tac monoclonal antibody (mAb) developed by our group for the treatment of ATL. The scientific basis for these therapeutic studies is that the leukemic cells of patients with ATL express abnormally high levels of the Tac antigen (IL-2R alpha) on their surface whereas resting normal cells including normal T-cells of the patients do not. One presumed mode of action of Hu-anti-Tac in the treatment of ATL involves the interruption of the interaction of IL-2 with its growth factor receptor. To be effective in this goal we must maintain saturation of the IL-2 receptors (IL-2R) with humanized anti-Tac thereby preventing IL-2 mediated proliferation and yielding cytokine deprivation and apoptotic cell death of the leukemic cells. Eligible patients with ATL will be treated with escalating doses of Zenapax® (Registered Trademark) between groups in the Clinical Center of the NIH. Groups of patients will receive sufficient Zenapax® (Registered Trademark) to yield saturation of the IL-2 receptor for a period of 17 weeks. Following an initial loading dose, the responding patients will receive subsequent doses at week 2 and then at 3 week intervals for a total of 6 doses. Clinical response will be evaluated using routine immunological and clinical evaluation and by monitoring the saturation of the IL-2R and the absolute number of residual circulating malignant cells by FACS analysis using two fluorochrome-labeled non-crossreacting antibodies to the IL-2 receptor, anti-Tac and 7G7/B6, as well as antibodies to CD3, CD4, CD7, and CD8. Furthermore, responses will be evaluated in patients with leukemia by Southern blot analysis of the arrangement of the T-cell receptor genes and HTLV-I integration. Finally, in select patients, to define the pharmacokinetics of the therapeutic antibody, we plan to monitor the serum levels of the infused Hu-anti-Tac (Zenapax® (Registered Trademark)) as a function of time. This study is an essential element of our program involving IL-2R-directed therapeutic studies. If as anticipated the therapy with humanized anti-Tac yields some partial and complete remissions in patients with ATL, we will propose that it be used as a single agent for patients with smoldering and chronic ATL and in association with chemotherapeutic agents to provide a novel approach for the treatment of acute and lymphoma forms of ATL. In a subsequent addition to this protocol, we will propose that patients not manifesting a remission with Zenapax® (Registered Trademark) alone will cross over to a therapeutic regimen that includes saturating doses of Zenapax® (Registered Trademark) as well as additional agents directed toward ATL (e.g., zidovudine (AZT)/IFN). We also plan a future clinical trial where we will evaluate the efficacy and toxicity in ATL patients of saturating doses of Zenapax® (Registered Trademark) as compared to identical doses of Zenapax® (Registered Trademark) given in association with (90)Y-armed 7G7/B6, a non-competing antibody to IL-2R alpha or in combination with chemotherapy.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA

Patients diagnosed with any stage of HTLV-I-associated adult T-cell leukemia.

Patients must have serum antibodies directed to HTLV-I.

All patients must have a histologically confirmed diagnosis of adult T-cell leukemia/lymphoma.

At least 5 percent of each patient's peripheral blood, lymph node, pulmonary or dermal malignant cells must react with the anti-Tac mAb as determined by immunofluorescent staining or, alternatively, the serum-soluble IL-2 receptor levels must be greater than 1,000 units/ml.

All stages of Tac-expressing adult T-cell leukemia are eligible including smoldering, chronic, lymphoma or acute ATL.

Patients must have measurable disease. All patients with greater than 5 percent abnormal (i.e., Tac homogenous strongly expressing) PBMC in the peripheral blood will be deemed to have measurable disease.

The patient must have a granulocyte count of at least 500/mm(3) and a platelet count of 25,000/mm(3).

Patients must have a creatinine of less than 3.0 mg/dl.

Patients must have a Karnofsky performance score of greater than 60 percent.

ATL patients without, as well as those with, previous chemotherapy will be eligible for inclusion in the study.

Patients with previous therapy with a monoclonal antibody including anti-Tac will be eligible for the study provided that they do not have a positive HAHA (human antibody to humanized anti-Tac) value (i.e., such patients must have a value greater than 250 ng/ml).

Omission of cytotoxic chemotherapy for ATL for 3 weeks prior to entry into the trial is required. However, patients receiving corticosteroids will not be excluded.

Patients must have a life expectancy of greater than 2 months.

Eligible patients must be greater than or equal to 10 years old. There is no upper age limit.

Patients over the age of 18 years must be able to understand and sign an Informed Consent form.

Eligible minors greater than 10 years old must give assent to participate in this study.

EXCLUSION CRITERIA:

Patients with symptomatic central nervous system disease that is due to the adult T-cell leukemia will be excluded. However, patients that have both ATL and another HTLV-I-associated disease, tropical spastic paraparesis (TSP), will be included. Tac-expressing T cells may be present in the CSF as long as the patient does not have symptomatic CNS disease.

Pregnant and/or nursing patients are not eligible for the study.

HIV positive patients are excluded from the study.

Patients with SGOT or SGPT values 5.0-fold greater than the upper limit of normal or bilirubin greater than 2.9 mg/dl will be excluded.

Special Instructions: Currently Not Provided

Keywords:

Interleukin-2 Receptor alpha chain

Interleukin-2

HTLV-I

Adult T-Cell Leukemia (ATL)

Monoclonal Antibody (Daclizumab, Zenapax)

Recruitment Keywords:

None

Conditions:

HTLV-I Infection

T Cell Leukemia

Investigational Drug(s):

Humanized Anti-Tac

Investigational Device(s):

None

Contacts:

Wendy Gao, R.N.
National Institutes of Health
Building 10
Room 4N115
10 Center Drive
Bethesda, Maryland 20892
Phone: (301) 402-1898
Fax: (301) 402-1001

Electronic Address: gaowe@mail.nih.gov

Citations:

Continuous cultures of fused cells secreting antibody of predefined specificity

Tumor therapy with monoclonal antibodies

Monoclonal antibodies for cancer therapy

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