• Clinical tumor regression [ Designated as safety issue: No ]
• Toxicity profile [ Designated as safety issue: Yes ]

• Clinical tumor regression
• Toxicity profile

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).

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.

• Biological: aldesleukin
• Biological: filgrastim
• Biological: incomplete Freund's adjuvant
• Biological: interleukin-2 gene
• Biological: therapeutic tumor infiltrating lymphocytes
• Drug: cyclophosphamide
• Drug: fludarabine phosphate

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