RATIONALE: Monoclonal antibodies such as siplizumab can locate cancer cells and either kill
them or deliver cancer-killing substances to them without harming normal cells.
PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of
siplizumab in treating patients with lymphoproliferative disorders.
- 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.
- 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 unacceptable 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
PROJECTED ACCRUAL: A total of 88 patients will be accrued for this study.
- 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
- 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
- 18 and over
- Karnofsky 70-100%
- More than 2 months
- 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
- SGOT and SGPT ≤ 2.0 times upper limit of normal (ULN) (5 times ULN for patients with
- 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
- Creatinine ≤ 1.5 mg/dL OR
- Creatinine clearance > 60 mL/ min by 24-hour urine collection
- 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
- Oxygen saturation level at least 90% by pulse oximetry
- No respiratory insufficiency requiring oxygen therapy
- 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
- 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:
- 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
- See Disease Characteristics
- At least 3 weeks since prior cytotoxic chemotherapy and recovered
- No concurrent FDA-approved or investigational cancer chemotherapeutic agents
- At least 3 weeks since prior prolonged cytolytic steroid therapy and recovered
- No concurrent steroids
- Not specified
- At least 3 weeks since prior surgery and recovered
- At least 30 days since other prior investigational anticancer drugs
- No other concurrent investigational anticancer drugs