Cyclophosphamide and Fludarabine Followed By an Autologous Lymphocyte Infusion and Interleukin-2 in Treating Patients With Refractory or Recurrent Metastatic Melanoma

Study Overview
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Brief Summary
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RATIONALE: An infusion of a patient's lymphocytes that have been treated in the laboratory to remove certain immune cells may be an effective treatment for melanoma. Drugs, such as cyclophosphamide and fludarabine, may suppress the immune system so that the patient's immune cells allow the infused lymphocytes to work. Interleukin-2 may help the lymphocytes kill more tumor cells when they are put back in the body. Giving cyclophosphamide and fludarabine followed by an autologous lymphocyte infusion and interleukin-2 may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cyclophosphamide and fludarabine followed by an autologous lymphocyte infusion and interleukin-2 works in treating patients with refractory or recurrent melanoma.

Detailed Description
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OBJECTIVES: Primary Determine tumor regression in patients with metastatic melanoma treated with nonmyeloablative lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine followed by autologous CD25-positive-T-regulatory-cell-depleted lymphocyte reinfusion and high-dose interleukin-2. Secondary Determine the rate of repopulation of CD25-positive T-regulatory cells in patients treated with this regimen. Determine the toxicity of this regimen in these patients. OUTLINE: Apheresis and CD25-positive T-regulatory cell depletion: Patients undergo 1-2 aphereses to collect peripheral blood mononuclear cells (PBMC). CD25-positive T-regulatory cells are depleted from the collected PBMC in vitro. Nonmyeloablative lymphodepleting chemotherapy: Patients receive cyclophosphamide IV over 1 hour on days -8 and -7 and fludarabine IV over 15-30 minutes on days -6 to -2. Autologous CD25-positive-T-regulatory-cell-depleted lymphocyte reinfusion: Patients receive autologous lymphocytes IV over 20-30 minutes on day 0. Filgrastim (G-CSF) and high-dose interleukin-2 (IL-2) therapy: Patients receive G-CSF subcutaneously (SC) daily beginning on day 0 and continuing until blood counts recover. Patients also receive high-dose IL-2 IV over 15 minutes 3 times daily on days 0-4 and 14-18. Patients are reevaluated 4-6 weeks after completion of high-dose IL-2 therapy. Patients achieving stable disease or a partial response may receive additional high-dose IL-2 as above for up to 2 retreatment courses in the absence of disease progression or unacceptable toxicity. Retreatment begins at least 6 weeks after autologous lymphocyte reinfusion. After completion of study treatment, patients are followed at 4-6 weeks and then every 1-2 months thereafter. PROJECTED ACCRUAL: A total of 16-29 patients will be accrued for this study within 1-1.5 years.

Official Title
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Phase II Trial Using Aldesleukin (IL-2) Following a Lymphodepleting Chemotherapy and Reinfusion of Autologous Lymphocytes Depleted of T Regulatory Lymphocytes in Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: aldesleukin
* Biological: filgrastim
* Biological: therapeutic autologous lymphocytes
* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of melanoma Metastatic disease Measurable disease HLA-A2 negative disease Disease did not respond to OR recurred after completion of prior high-dose interleukin-2 (IL-2) Eligible to receive high-dose IL-2 No tumor reactive cells available for cell transfer therapy PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy At least 3 months Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 8.0 g/dL No coagulation disorders Hepatic ALT and AST < 3 times upper limit of normal Bilirubin ≤ 2.0 mg/dL (< 3.0 mg/dL if due to Gilbert's syndrome) Hepatitis B surface antigen negative Hepatitis C antigen negative Renal Creatinine ≤ 2.0 mg/dL No renal failure requiring dialysis due to toxic effects of prior IL-2 administration Cardiovascular No myocardial infarction No cardiac arrhythmias No other major cardiovascular illness as evidenced by a positive stress thallium or comparable test Normal cardiac stress test (e.g., stress thallium, stress MUGA, dobutamine echocardiogram) AND LVEF ≥ 45% (for patients ≥ 50 years of age or who have a history of EKG abnormalities, symptoms of cardiac ischemia, or arrhythmias) Pulmonary No obstructive or restrictive pulmonary disease No other major respiratory illness FEV_1 ≥ 60% of predicted (for patients with a prolonged history of cigarette smoking or symptoms of respiratory dysfunction) Immunologic HIV negative Epstein-Barr virus positive No active systemic infection No autoimmune disease (e.g., autoimmune colitis or Crohn's disease) No immunodeficiency due to prior chemotherapy or radiotherapy Recovered immune competence after prior chemotherapy or radiotherapy as evidenced by normal lymphocyte count and WBC and an absence of opportunistic infection No other major immune system disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 4 months after completion of study treatment No other toxic effects during prior IL-2 administration that would preclude redosing with IL-2, including the following: Mental status changes that would require intubation Bowel perforation PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics At least 4 weeks since prior systemic therapy Chemotherapy At least 6 weeks since prior nitrosoureas At least 4 weeks since prior systemic therapy Endocrine therapy No concurrent systemic steroid therapy Radiotherapy Not specified Surgery Not specified

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: aldesleukin|nan|
|Biological: filgrastim|nan|
|Biological: therapeutic autologous lymphocytes|nan|
|Drug: cyclophosphamide|nan|
|Drug: fludarabine phosphate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor regression |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of repopulation of CD25-positive T-regulatory cells |  |  | 
| Toxicity |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent melanoma, stage IV melanoma