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

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.

- INCLUSION CRITERIA

All patients must have histologically or cytologically confirmed T-LGL leukemia as defined
by:

i. 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;

ii. 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.

iii. At least 50% of the CD3+/CD8+ cells must also express CD122 (IL-2/15RB plus).

iv. 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.

*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.

EXCLUSION CRITERIA

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.

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.