Cyclophosphamide and Fludarabine Followed By Interleukin-2 Gene-Modified Tumor Infiltrating Lymphocytes in Treating Patients With Metastatic Melanoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as cyclophosphamide and fludarabine use different ways to stop tumor cells from dividing so they stop growing or die. Inserting the gene for interleukin-2 into a person's tumor infiltrating lymphocytes may make the body build an immune response to kill tumor cells. Combining cyclophosphamide and fludarabine with gene-modified tumor cells may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of gene-modified tumor infiltrating lymphocytes when given together with cyclophosphamide and fludarabine and to see how well they work in patients with metastatic melanoma (phase I is closed to accrual 3/29/06).

Detailed Description
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OBJECTIVES: Primary Determine the survival of patients with metastatic melanoma administered interleukin-2 gene-modified tumor infiltrating lymphocytes after cyclophosphamide and fludarabine. Compare survival results with prior Surgery Branch studies using adoptive cell therapy without the interleukin-2 retroviral vector (SBIL-2) gene. Secondary Determine clinical tumor regression in patients administered interleukin-2 gene-modified TIL after cyclophosphamide and fludarabine followed by interleukin-2. Determine the toxicity profile of this regimen in these patients. OUTLINE: Phase I (closed to accrual as of 3/29/06): Harvest: TIL are harvested, transduced with IL-2 gene, and expanded in vitro over a period of approximately 4 weeks. Nonmyeloablative preparative regimen (chemotherapy): Patients receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to -1. Lymphocyte administration: Patients receive IL-2 gene-transduced TIL IV over 20-30 minutes on day 0. They also receive high-dose IL-2 IV over 15 minutes every 8 hours on days 0 -5 (maximum 15 doses). Beginning 1-2 days after lymphocyte administration, patients receive filgrastim (G-CSF) subcutaneously (SC) daily, , until blood counts recover. Retreatment: Patients are re-evaluated every 4-6 weeks. Retreatment depends on disease status after each regimen. Patients with dose-limiting toxicity do not receive further treatment. No response: Patients with stable disease or disease progression after the initial treatment are followed or removed from the study. Partial response: Patients with a partial or minor response after the initial treatment may receive retreatment, approximately 2-4 weeks later, with chemotherapy, IL-2 gene-transduced TIL, immunization, and high-dose IL-2 as above, every 4-6 weeks for up to 2 courses provided at least a partial response is documented after each regimen. Complete response: Patients with a complete response receive no further treatment. Phase II: Patients receive treatment and retreatment as in phase I with the MTD of IL-2 gene-transduced TIL. Patients are followed every 3-6 weeks in the absence disease progression. PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

Official Title
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Tumor Infiltrating Lymphocytes (TIL Cells) Transduced With An Interleukin-2 (SBIL-2) Gene Following The Administration Of A Nonmyeloablative But Lymphocyte Depleting Regimen in Metastatic Melanoma

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: aldesleukin
* Biological: filgrastim
* Biological: incomplete Freund's adjuvant
* Biological: interleukin-2 gene
* Biological: therapeutic tumor infiltrating 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 Refractory to standard therapy including high-dose interleukin-2 (IL-2) therapy Evaluable disease Patients may enroll at the cell infusion stage provided they have tumor available for biopsy OR expandable SBIL-2-transduced tumor infiltrating lymphocytes available Progressive disease during prior immunization to melanoma antigens or cellular therapy, with or without myeloablation, allowed Symptomatic CNS lesions allowed provided immediate active treatment for symptomatic lesions has been completed PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy More than 3 months Hematopoietic Absolute neutrophil count greater than 1,000/mm^3 WBC greater than 3,000/mm^3 Lymphocyte count greater than 500/mm^3 Platelet count greater than 100,000/mm^3 Hemoglobin greater than 8.0 g/dL No coagulation disorder Hepatic Bilirubin no greater than 2.0 mg/dL (less than 3.0 mg/dL in patients with Gilbert's syndrome) AST/ALT less than 3 times upper limit of normal Hepatitis B surface antigen negative Hepatitis C virus negative Renal Creatinine no greater than 1.6 mg/dL Cardiovascular No myocardial infarction No cardiac arrhythmias No abnormal stress thallium or comparable test LVEF > 45% and normal stress cardiac test in patients with the following criteria: 50 years old or greater History of EKG abnormalities, symptoms of cardiac ischemia or arrhythmias No major cardiovascular illness Pulmonary No obstructive or restrictive pulmonary disease No major respiratory illness FEV_1 > 60% predicted in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction Immunologic HIV negative No prior severe immediate hypersensitivity reaction No primary or secondary immunodeficiency No active systemic infection No concurrent opportunistic infection No major immune system illness Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 4 months after study therapy Must sign a durable power of attorney PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No prior anti-cytotoxic T-lymphocyte antibody-4 antibody (CTLA-4) allowed unless post-MDX010 treatment and colonoscopy with colonic biopsies are normal Chemotherapy Recovered from prior chemotherapy Endocrine therapy No concurrent steroids Radiotherapy Recovered from prior radiotherapy Surgery Not specified Other More than 4 weeks since prior systemic therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: incomplete Freund's adjuvant|nan|
|Biological: interleukin-2 gene|nan|
|Biological: therapeutic tumor infiltrating 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 |
| --- | --- | --- |
| Survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical tumor regression |  |  | 
| Toxicity profile |  |  | 

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