• Safety and maximum tolerated dose at study completion then every 3 months for 1 year [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of siplizumab (MEDI-507) in patients with CD2-positive lymphoproliferative disorders.
• Determine the safety and tolerability of this drug in these patients.

Secondary

• Determine the time to MEDI-507 saturation of CD2-binding sites in peripheral blood and tumor aspirates of these patients.
• Determine the serum pharmacokinetics of this drug in these patients.
• Determine the time to T-cell and natural killer cell depletion and recovery in patients after treatment with this drug.
• Determine the antitumor activity of this drug, in terms of response rate, time to progression, and overall survival, in these patients.

OUTLINE: This is an open-label, dose-escalation study.

Patients receive siplizumab (MEDI-507) IV over 4 hours on days 1 and 2 every 2 weeks for 16 weeks OR on days 1-3 every 2 weeks for 16 weeks OR on days 1 and 14, then weekly for 16 weeks in the absence of disease progression or unacceptable toxicity. Patients with a positive treatment response (e.g., stable disease, minor response, partial response, or complete response) after 16 weeks of treatment may continue to receive MEDI-507 as above in the absence of disease progression or unaccebtable toxicity.

Cohorts of 3-6 patients receive escalating doses of MEDI-507 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After completion of treatment, patients are followed at 30 days and then every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 88 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed lymphoproliferative disorder, including the following types:

  • Adult T-cell leukemia

    • No smoldering leukemia

  • Cutaneous T-cell lymphoma

    • All stages, excluding stage Ia
    • Patients with stage Ib, II, or III disease must have failed at least 1 prior standard therapy regimen

  • Peripheral T-cell lymphoma

    • Stage I-IV
    • Disease progression after standard chemotherapy

  • Large granular lymphocyte leukemia meeting the following criteria:

    • Must have 1 of the following:

      • Myelosuppression based on at least 1 of the following laboratory values:

        • Granulocyte count no greater than 1,500/mm^3
        • Platelet count no greater than 75,000/mm^3
        • Hemoglobin no greater than 10 g/dL
      • Requirement for hematopoietic support (e.g., transfusion or colony-stimulating factors, including filgrastim [G-CSF], interleukin-11, or epoetin alfa) to maintain blood levels or control systemic symptoms (e.g., fever, night sweats, or weight loss)
    • Disease unresponsive to 1 prior therapy regimen
    • Monoclonal and polyclonal forms of disease allowed

• CD2-positive by immunohistochemistry

  • At least 30% of tumor cells must express CD2
• Measurable or evaluable disease
• No history of CNS disease

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 70-100%

Life expectancy

• More than 2 months

Hematopoietic

• See Disease Characteristics
• Granulocyte count at least 1,000/mm^3*
• Platelet count at least 50,000/mm^3* NOTE: *Requirement waived for patients with large granular lymphocyte leukemia

Hepatic

• SGOT and SGPT ≤ 2.0 times upper limit of normal (ULN) (5 times ULN for patients with Gilbert's syndrome)
• Bilirubin ≤ 2.0 mg/dL (3.5 times ULN for patients with Gilbert's syndrome)
• Hepatitis B surface antigen negative
• No positive antibodies to hepatitis C virus

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance > 60 mL/ min by 24-hour urine collection

Cardiovascular

• No myocardial infarction within the past 6 months
• No uncontrolled hypertension within the past 6 months
• No stroke or transient ischemic attack within the past 6 months

Pulmonary

• Oxygen saturation level at least 90% by pulse oximetry
• No respiratory insufficiency requiring oxygen therapy

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• Symptomatic cytomegalovirus (CMV) negative or CMV PCR ≤ 1000 copies
• No history of significant adverse events related to previously administered monoclonal antibody
• No active infection requiring systemic anti-infective therapy
• No physical or general medical illness that would increase risk to the patient
• No psychological or behavioral condition that would increase risk to the patient or preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 30 days since prior monoclonal antibody therapy
• No prior siplizumab (MEDI-507)
• No other concurrent monoclonal antibody therapies
• No other concurrent biologic response modifier therapy
• No concurrent gamma globulin
• Concurrent G-CSF, epoetin alfa, and interleukin-11 allowed for large granular lymphocyte leukemia

Chemotherapy

• See Disease Characteristics
• At least 3 weeks since prior cytotoxic chemotherapy and recovered
• No concurrent FDA-approved or investigational cancer chemotherapeutic agents

Endocrine therapy

• At least 3 weeks since prior prolonged cytolytic steroid therapy and recovered
• No concurrent steroids

Radiotherapy

• Not specified

Surgery

• At least 3 weeks since prior surgery and recovered

Other

• At least 30 days since other prior investigational anticancer drugs
• No other concurrent investigational anticancer drugs