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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

Phase 1/Phase 2
10 Years
Not Enrolling
HTLV-I Infection, T Cell Leukemia

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Trial Information

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


Human T-lymphotropic virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL)
is an aggressive lymphoproliferative disorder.

Chemotherapy has had limited impact on survival.

The interleukin 2 receptor alpha (IL-2R alpha) (CD25) is over expressed on ATL cells and the
smoldering and chronic stages of ATL are often interleukin 2 (IL-2) dependent.

The monoclonal antibody daclizumab (Zenapax) inhibits interleukin 2 (IL-2) binding to its

It is hypothesized that daclizumab may inhibit ATL growth.


To determine the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac
(daclizumab, Zenapax) in patients with ATL.

To define the dose of Zenapax required to saturate IL-2R alpha in patients with ATL.

To determine the clinical response to humanized (Hu) anti-Tac (Zenapax) of patients with
Tac-expressing smoldering and chronic stage adult T cell leukemia.

To determine the serum dieaway curve (pharmacokinetics) of infused humanized (Hu) - anti -
Tac in patients who have ATL.


Smoldering and chronic stage HTLV-1-associated adult T cell leukemia.

At least 5 percent of malignant cells in the peripheral blood or lymph nodes must react with
the anti-Tac (CD25) antibody.

Age greater than or equal to 10-years-old.

Patients must have measurable disease.

Patients with and without prior treatment.

Patients must have a granulocyte count of greater than or equal to 500/micro L,

platelets greater than or equal to 25,000/micro L,

and creatinine less than 3.0 gm/dL.


Phase I patients on cohorts 1-4 received the following: cohort 1: 2 mg/kg over 60 minutes
intravenously on days 1 and 2; cohort 2: 4 mg/kg over 90 minutes intravenously on day 1,
single dose; cohort 3: 6 mg/kg over 90 minutes intravenously on day 1, single dose; and
cohort 4: 8 mg/kg over 90 minutes intravenously on day 1, single dose.

Patients with smoldering or chronic stage ATL will be treated with intravenous daclizumab 8
mg/kg on day 0 and weeks 2, 5, 8, 11 and 14.

Patients achieving a response will continue on treatment with daclizumab 8 mg/kg every 3
weeks for up to 24 months.

Patients achieving a complete response (CR) will continue on treatment with daclizumab
8mg/kg every 3 weeks for up to 24 months.

Patients achieving a partial response (PR) will be maintained on daclizumab 8 mg/kg
administered every 3 weeks provided the PR is maintained and no serious adverse event or
toxicity related to daclizumab therapy is observed.

Inclusion Criteria


- Population Base.

- Patients diagnosed with smoldering or chronic human T-lymphotropic virus type 1
(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

- 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 interleukin 2 (IL-2)
receptor levels must be greater than 1,000 units/ml (normal geometric mean, 235; with
a 95% confidence interval of 112 to 502 units/mL).

- Smoldering or chronic stage Tac-expressing adult T-cell leukemia defined by the
Shimomyama Criteria (37) are eligible.

- To be diagnosed as smoldering Adult T-cell Leukemia (ATL), the patient must have a
normal lymphocyte count (less than 4 times 10^3/mm^3), less than or equal to 5
percent abnormal lymphocytes on morphologic examination of the peripheral blood smear
or on fluorescence activated cell sorting (FACS) analysis (cells with a homogenous
staining pattern and a greater than 1 log increase in the magnitude of fluorescence
emission of the anti-Tac peak over background expression),

- no hypercalcemia,

- lactate dehydrogenase less than or equal to 1.5 times the upper limit of normal,

- no lymphadenopathy,

- no involvement of extra nodal organs except skin or lung and no malignant pleural
effusion or ascites.

- If the abnormal lymphocyte count is less than 5 percent, the patient must have at
least one histologically proven skin ATL lesion to be diagnosed as smoldering ATL.

- Patients with >5% of circulating lymphocytes that are abnormal are considered 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

- 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 or equal to 10 years old must give assent to participate
in this study.


- 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.

- Furthermore, Tac-expressing T cells may be present in the cerebrospinal fluid (CSF)
as long as the patient does not have symptomatic central nervous system (CNS)

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

- Human immunodeficiency virus (HIV) positive patients are excluded from the study.

- Patients with serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic
pyruvic transaminase (SGPT) values 5.0-fold greater than the upper limit of normal or
bilirubin greater than 2.9 mg/dl will be excluded.

- 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.

- Acute or Lymphoma stage HTLV-1 associated adult T cell leukemia.

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Duration of Response

Outcome Description:

Duration of response was defined as the interval from the time response is first achieved to the time progression from the best response is detected. Responses are assessed by a modified World Health Organization (WHO) criteria. Partial response is a reduction of >=50% saturation in the circulating leukemic cell count; complete response is disappearance of all measurable and non-measurable disease lasting more than 1 month; stable disease is patients who did not meet the criteria; and progressive disease is a >=25% increase in leukemic cell count.

Outcome Time Frame:

21-220 weeks

Safety Issue:


Principal Investigator

Thomas Waldmann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

December 1999

Completion Date:

February 2011

Related Keywords:

  • HTLV-I Infection
  • T Cell Leukemia
  • Interleukin-2 Receptor alpha chain
  • Interleukin-2
  • HTLV-I
  • Adult T-Cell Leukemia (ATL)
  • Monoclonal Antibody (Daclizumab, Zenapax)
  • HTLV-I Infections
  • Leukemia
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892