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T-Cell Large Granular Lymphocytic LeukemiaPhase 1NCT00076180

Hu-Mik-beta1 to Treat T-Cell Large Granular Lymphocytic Leukemia

A Phase 1 study testing Hu-MiK-Beta-1 in people with T-Cell Large Granular Lymphocytic Leukemia and Leukemia, T-Cell Large Granular Lymphocytic, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study will examine the use of the humanized Mik-beta-1 (Hu-Mik-beta1) antibody in patients with T-cell large granular lymphocytic leukemia (T-LGL). Patients with T-LGL often have reduced white blood cells, red blood cells, and platelets, and increased numbers of abnormal cells called large granular lymphocytes… Read more about this study

Who is it for?
Ages 18 to 99 years
What is being tested?
Hu-MiK-Beta-1
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteUnited States
Study dates
1 Mar 2004to 9 Jan 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • All patients must have histologically or cytologically confirmed T-LGL leukemia as defined by:
  • A peripheral blood smear or bone marrow biopsy/aspirate with morphological findings consistent with LGL as determined by Hematopathology section, the NIH Clinical Center, or the Laboratory of Pathology, NCI, and;
  • An absolute C3+, CD8+, usually CD57+ cell (T-LGL) count greater than or equal to 1000/uL in the peripheral blood or bone marrow as measured by flow cytometry.
  • At least 50% of the CD3+/CD8+ cells must also express CD122 (IL-2/15RB plus).
  • Clonal T cell receptor (TcR) rearrangement while desirable, is not a requirement for eligibility. TcR rearrangement may be determined by Southern blotting or polymerase chain reaction (PCR).
  • Patients must have T-LGL-associated hemocytopenia(s) as defined by an absolute granulocyte count (AGC) less than 1000/uL, platelet count less than100,000/uL or hemoglobin less than 9.0 gm/dL, or have required transfusion of 3 or more units of red blood cell products in the last 6 months, or any combination of these.
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  • Patients being treated with a stable dose of hemopoietic growth factors for greater than 4-weeks whose peripheral blood counts exceed these values are eligible for the study. A stable dose of a hematopoeitic growth factor(s) may be continued while the patient is on the study.
  • Patients requiring antibiotic or treatment with antiviral drugs on more than two occasions over the previous 12 months for bacterial or viral infections associated with their LGL are eligible.
  • Patients must be greater than or equal to 18 years of age.
  • Untreated patients as well as those previously treated with cyclosporine A (CsA), chemotherapy, corticosteroids, interferon, erythropoietin, IL-11, G-CSF or GM-CSF, murine MiK-Beta-1 (or having undergone splenectomy are eligible for study.
  • Omission of cyclosporine A, chemotherapy and interferon is required for at least 4 weeks prior to entry onto the trial. Patients on stable doses (greater than 4 weeks) of commercial erythropoietin, G-CSF, GM-CSF or IL-11 products are eligible for the study. Patients receiving corticosteroids will not be excluded. Patients receiving corticosteroids must be on a stable dose of prednisone (less than 25 mg/day) or equivalent dose steroid for at least 3 weeks before receiving MiK-B -1 on the study.
  • Patients must have normal renal function (serum creatinine less than or equal to 1.5 mg/dL) and hepatic function (bilirubin less than or equal to 2.0 mg/dL, SGOT, SGPT less than or equal to 2.5 fold greater than the upper limit of normal).
  • Patients must have a Karnofsky performance status of greater than or equal to 70%.
  • Patients must have a life expectancy greater than 2 months.
  • Patients must be able to understand and sign the Informed Consent Document.

Who cannot join

  • Patients must have none of the following at the time of enrollment:
  • Symptomatic central nervous system (CNS) involvement with LGL leukemia.
  • Pregnant or actively nursing patients are ineligible. The effects of Hu-MiK-Beta-1 on the developing fetus and nursing infant are unknown. Female patients of childbearing potential will be tested for pregnancy within 72 hours of initiating the study.
  • Patients with CTC grade 4 granulocytopenia or anemia.
  • Patients requiring platelet transfusions in the preceding 12-months for platelet counts of less than or equal to 10,000/mm(3) or spontaneous bleeding episodes.
  • Patients testing positive for the human immunodeficiency virus (HIV) or human T cell lymphotrophic virus (HTLV-I/II) are ineligible, because the toxicity may be different in this population.
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  • Patients testing positive for hepatitis B virus surface antigen (HbsAg) or antibodies to hepatitis C virus are ineligible because Hu-MiK-Beta-1 therapy might be associated with increased viral replication.
  • Patients receiving prior therapy with murine MiK-Beta-1 that have developed human anti-mouse (HAMA) or human anti-human (HAHA) antibodies, or that have experienced CTC grade III or greater toxicity attributable to the antibody are ineligible.
  • Patients with a prior history of a Grade III or greater allergic reaction related to a previously administered humanized monoclonal antibody are ineligible.
  • Patients with other serious concurrent medical conditions (e.g., acute myocardial infarction within 6 months, unstable angina, NYHA Class II/IV congestive heart failure, respiratory insufficiency requiring oxygen therapy, uncontrolled hypertension, symptomatic cerebrovascular disease or stroke within 6 months, receiving immunosuppression for an organ graft, etc.) that may otherwise limit their survival are not eligible.
  • Other malignancy within five years, unless the probability of recurrence of the prior malignancy is less than or equal to 10 percent at 5-years. Patient's curatively treated for squamous cell carcinoma and basal cell carcinoma of the skin and carcinoma in situ of the uterine cervix (CIN) or patients with a history of malignant tumor in the past that have been disease free for at least five years are also eligible for this study.
  • Patients with serious active infection requiring systemic anti-infective therapy.
  • Any physical or psychological condition that would preclude drug administration or patient compliance with the protocol or that in the opinion of the investigator may pose an additional risk in administering the study drug to the patient or that would not permit the patient to complete the study or give Informed Consent.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Phase I Open-Label Single-Dose Study of Humanized Mik-Beta-1 Monoclonal Antibody Directed Toward the IL-2R/IL-15R-Beta Subunit (CD122) in T Cell Large Granular Lymphocytic Leukemia

This study will examine the use of the humanized Mik-beta-1 (Hu-Mik-beta1) antibody in patients with T-cell large granular lymphocytic leukemia (T-LGL). Patients with T-LGL often have reduced white blood cells, red blood cells, and platelets, and increased numbers of abnormal cells called large granular lymphocytes (LGLs). Patients may have recurrent infections, anemia, or abnormal bleeding. Hu-Mik-beta1 attaches to LGL cells and blocks the action of growth factors called interleukins that stimulate LGL growth. Blocking these interleukins may stop T-LGL leukemia cells from growing. This study will determine the dose and frequency of treatment with Hu-Mik-(SqrRoot) 1 that can safely be given to patients to coat the surface of their leukemic cells with antibody, determine how long the antibody lasts in the blood after injection, and examine the side effects and possible benefits of the drug in these patients.

Patients age 18 or older with T-LGL may be eligible for this study. Candidates will be screened with a medical history and physical examination, review of pathology studies, skin biopsy, evaluation of rheumatoid arthritis if present, chest x-ray, computerized tomography (CT) scans and other imaging studies as needed, bone marrow biopsy, and blood and urine tests.

Read more

Participants will receive a single dose of Hu-Mik-beta1 by a 90-minute infusion through a vein. Groups of patients will be treated with increasing doses (0.5, 1.0, and 1.5 mg/kg) of the antibody. Patients who develop serious drug side effects are taken off the study. The treatment requires a 3- to 4-day hospital stay. In addition to Hu-Mik-(SqrRoot) 1 treatment, patients will undergo the following tests and procedures:

  • Collection of blood for 8 days following the dose of Hu-Mik-beta1 to measure blood levels of the antibody.
  • Follow-up visits of 1 to 2 days at 22, 29, and 43 days after the dose of the antibody and then every 3 months for a total of 9 months.
  • Bone marrow aspirate and biopsy if one has not been done within 6 weeks before entering the study, and a repeat biopsy if complete remission of T-LGL is achieved after completing treatment. For the biopsy, an area of the hip is numbed and a special needle is used to draw bone marrow from the hipbone.
  • Imaging studies, such as chest x-ray and CT scan of the body after completing treatment if the screening scans showed abnormalities due to the T-LGL leukemia.
  • Lymph node biopsy in individuals with enlarged superficial lymph nodes due to T-LGL leukemia to see if the treatment is reaching the leukemia in the lymph nodes.

There may or may not be a direct benefit from participating in this study. However, the results may help in the treatment of future patients.

Read the detailed description

Background:

  • T cell large granular lymphocyte (T-LGL) leukemia is a chronic lymphoproliferative disorder associated with granulocytopenia, anemia and/or thrombocytopenia.
  • Although agents such as cyclosporine and methotrexate have shown activity in T-LGL, treatment of T-LGL has remained largely undefined and symptomatic.
  • The shared IL-2R/Il-15R Beta receptor (CD122) is over expressed on T-LGL cells and may stimulate growth T-LGL cells through its interaction with IL-15.
  • Hu-Mik-Beta1 is a humanized monoclonal antibody that binds to IL-2R/IL-15R Beta
  • Hu-Mik-Beta1 may inhibit the growth and exert cytotoxic activity against T-LGL cells.

Objectives:

  • To determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of Hu-Mik-Beta1 when administered to patients with T-LGL.
  • To determine the dose of Hu-Mik-Beta1 required to saturate IL-2R/IL-15R Beta (CD122) on -T-LGL cells in the peripheral blood.
  • To determine the pharmacokinetics and serum die-away curve of Hu-Mik-Beta1.
  • To provide preliminary information on the clinical response following single dose administration of Hu-MiK-Beta1 in patients with CD122 expressing T-LGL leukemia.

Eligibility:

--T cell large granular lymphocyte leukemia (T-LGL).

Patients must have a granulocyte count of less than 1000/microL, or hemoglobin less than 10 gm/dL, or be transfusion dependent, or platelets less than 100,000/ microL, or any combination of these unless receiving a hematopoietic growth factor.

  • T-LGL cell count greater than or equal to 1000/microL (CD3 plus/CD8 plus/usually CD57 plus) by flow cytometry.
  • Patients may be receiving a stable dose of a hematopoietic growth factor.

Design:

  • Cohorts of 3 patients each will be treated with a single intravenous dose of Hu-Mik-Beta1 at 0.5, 1.0 or 1.5 mg/kg.
  • Patients will be observed for adverse events for 6-weeks.
  • Detailed pharmacokinetic studies and determination of CD122 receptor saturation will be performed.
  • Response will be evaluated using hematological, flow cytometry, molecular and clinical evaluations.
  • An additional 3 patients will be accrued at the highest dose or MTD to aid in design of a Phase II trial.
  • Patients participating in Phase I will also be eligible to participate in Phase II.
Being tested
Hu-MiK-Beta-1
Keywords
cytotoxic activity against T-LGL cells, chronic lymphoproliferative disorder, T-LGL Leukemia, Natural Killer Cells, Leukemia, Lymphocytic Leukemia, T-LGL
Medical subject headings
Leukemia, Large Granular Lymphocytic, Leukemia, Leukemia, Lymphoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Hu-MiK-Beta-1Biological

    Hu-MiK-Beta-1 administered as an intravenous infusion over 90- minutes.

Study groups in NCT00076180
Study groupRoleWhat they receive
1ExperimentalOne dose of Hu-MiK Beta-1
Receives: Biological: Hu-MiK-Beta-1

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. DLT and MTD of Hu MIK Beta 1

    Adverse events will be tabulated/reported by type, grade, and frequency.

    Measured: 21 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jan 2004 (estimated)
  2. Study start1 Mar 2004
  3. Primary completion12 Nov 2010
  4. Study completion9 Jan 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Intervention model
Sequential
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00076180
Sponsor's protocol ID
040089
Other IDs
04-C-0089
Status last verified
9 Jan 2019
First submitted
14 Jan 2004
Last updated
11 Jan 2019
Results posted
No
FDA-regulated drug
Yes

Publications

  • Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7. doi: 10.1038/256495a0. No abstract available.

    PubMed 1172191

  • Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature. 1986 May 29-Jun 4;321(6069):522-5. doi: 10.1038/321522a0.

    PubMed 3713831

  • Waldmann TA. Monoclonal antibodies in diagnosis and therapy. Science. 1991 Jun 21;252(5013):1657-62. doi: 10.1126/science.2047874.

    PubMed 2047874

  • Waldmann TA, Conlon KC, Stewart DM, Worthy TA, Janik JE, Fleisher TA, Albert PS, Figg WD, Spencer SD, Raffeld M, Decker JR, Goldman CK, Bryant BR, Petrus MN, Creekmore SP, Morris JC. Phase 1 trial of IL-15 trans presentation blockade using humanized Mikbeta1 mAb in patients with T-cell large granular lymphocytic leukemia. Blood. 2013 Jan 17;121(3):476-84. doi: 10.1182/blood-2012-08-450585. Epub 2012 Dec 3.

    PubMed 23212516

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Hu-MiK-Beta-1 in people with T-Cell Large Granular Lymphocytic Leukemia and Leukemia, T-Cell Large Granular Lymphocytic, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

DLT and MTD of Hu MIK Beta 1 (time frame: 21 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00076180, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2019.

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