Patient case: 49-year-old male with melanoma; genetic feature: extensive tumor infiltrating lymphocytes

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

Summary: 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: 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.

Eligibility: 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

Relevance to patient case: possibly relevant