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Anti-Tac for Treatment of Leukemia

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00001941
First Posted: January 19, 2000
Last Update Posted: August 20, 2012
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
National Institutes of Health Clinical Center (CC)
  Purpose
The purpose of the study was to determine: (1) the toxicity and maximum tolerated dose (MTD) of humanized anti-Tac (daclizumab), (Zenapax(Registered Trademark)) in patients with adult T-cell leukemia/lymphoma (ATL); (2) to define the dose of Zenapax(Registered Trademark) required to saturate interleukin 2 receptor alpha (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 represented an extension of Metabolism Branch National Cancer Institute (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 interleukin 2 (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 were treated with escalating doses of Zenapax(Registered Trademark) between groups in the Clinical Center of the National Institutes of Health (NIH). Groups of patients received sufficient Zenapax(Registered Trademark) to yield saturation of the IL-2 receptor for a period of 17 weeks. Clinical response was 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 fluorescence activated cell sorting (FACS) analysis using two fluorochrome-labeled non-crossreacting antibodies to the IL-2 receptor, anti-Tac and 7G7/B6, as well as antibodies to cluster of differentiation 3 (CD3), cluster of differentiation 4 (CD4), cluster of differentiation 7 (CD7), and cluster of differentiation 8 (CD8). Furthermore, responses were evaluated in patients with leukemia by Southern blot analysis of the arrangement of the T-cell receptor genes and human T-lymphotropic virus type 1 (HTLV-I) integration. Finally, in select patients, to define the pharmacokinetics of the therapeutic antibody, had planned 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. We also plan a future clinical trial where tentative plans also had been made to 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.

Condition Intervention Phase
HTLV-I Infection T Cell Leukemia Biological: daclizumab Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Duration of Response [ Time Frame: 21-220 weeks ]
    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.

  • Overall Survival [ Time Frame: 132.6 weeks ]
    Measured from the time the patient is consented until death.

  • Percentage of Participants With an Overall Response Rate [ Time Frame: up to 220 weeks ]
    Participants overall response rate was defined as complete response (CR) + partial response (PR) from study consent until progression was measured. Responses was 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; and progressive disease is a >=25% increase in leukemic cell count

  • Number of Participants With Adverse Events [ Time Frame: 12 months ]
    Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.


Enrollment: 34
Study Start Date: December 1999
Study Completion Date: February 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I - 2 mg/kg cohort
2 mg/kg daclizumab over 60 minutes intravenously on days 1 and 2
Biological: daclizumab
Other Name: Zenapax
Experimental: Phase I - 4 mg/kg cohort
4 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose
Biological: daclizumab
Other Name: Zenapax
Experimental: Phase I - 6 mg/kg cohort
6 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose
Biological: daclizumab
Other Name: Zenapax
Experimental: Phase I - 8 mg/kg cohort
8 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose
Biological: daclizumab
Other Name: Zenapax
Experimental: Phase II - 8 mg/kg cohort
8 mg/kg daclizumab over 90 minutes intravenously on day 1, single dose
Biological: daclizumab
Other Name: Zenapax

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • ELIGIBILITY CRITERIA:
  • Population Base.
  • Patients diagnosed with smoldering or chronic human T-lymphotropic virus type 1 (HTLV-I)- associated adult T-cell leukemia.

INCLUSION CRITERIA:

  • 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 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 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 or equal to 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.
  • 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) disease.
  • 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001941


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas Waldmann, M.D. National Cancer Institute, National Institutes of Health
  More Information

Additional Information:
Publications:
Responsible Party: Thomas A. Waldmann, M.D./National Cancer Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00001941     History of Changes
Obsolete Identifiers: NCT00020020
Other Study ID Numbers: 000030
00-C-0030
First Submitted: January 18, 2000
First Posted: January 19, 2000
Results First Submitted: April 23, 2012
Results First Posted: August 9, 2012
Last Update Posted: August 20, 2012
Last Verified: August 2012

Keywords provided by National Institutes of Health Clinical Center (CC):
Interleukin-2 Receptor alpha chain
Interleukin-2
HTLV-I
Adult T-Cell Leukemia (ATL)
Monoclonal Antibody (Daclizumab, Zenapax)

Additional relevant MeSH terms:
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
HTLV-I Infections
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Deltaretrovirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Immunologic Deficiency Syndromes
Interleukin-2
Daclizumab
Immunoglobulin G
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors