Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma

OBJECTIVES:

Primary

• Determine complete clinical tumor regression in patients with metastatic melanoma treated with a myeloablative lymphoid-depleting preparative regimen comprising cyclophosphamide, fludarabine, and total body irradiation followed by autologous tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell transplantation, and low-dose or high-dose interleukin-2.
• Evaluate the safety of this regimen in these patients.

Secondary

• Determine the survival of the infused lymphocytes by analyzing the sequence of the variable region of the T-cell receptor or flow cytometry in patients treated with this regimen.

OUTLINE:

• Autologous stem cell collection: Patients receive filgrastim (G-CSF) subcutaneously (SC) twice daily for 8 days. Beginning on day 5 of G-CSF, patients undergo apheresis daily for up to 3 days. Patients may receive 1 additional course of G-CSF and apheresis or use stem cells stored from a prior stem cell harvest in order to obtain an adequate number of cells.
• Lymphocyte-depleting myeloablative preparative regimen: Patients receive cyclophosphamide intravenous (IV) over 1 hour on days -5 and -6 and fludarabine IV over 15-30 minutes on days -6 to -2. Patients also undergo total body irradiation on day -1.
• Autologous lymphocyte infusion: Patients receive autologous tumor-reactive tumor-infiltrating lymphocytes IV over 20-30 minutes on day 0* followed by G-CSF SC once daily until blood counts recover.
• Autologous stem cell transplantation: Patients receive autologous CD34+ stem cells IV on day 2.
• Interleukin therapy: Patients are assigned to 1 of 2 cohorts, depending on whether they have received prior high-dose interleukin-2 (IL-2).

• Cohort 1 (patients who received prior high-dose IL-2): Beginning on day 0*, patients receive high-dose IL-2 IV over 15 minutes 3 times daily for up to 5 days (maximum of 15 doses).
• Cohort 3 (patients who have not received prior high-dose IL-2): Patients receive treatment as in cohort 1.

NOTE: *Day 0 is 1-4 days after the last dose of fludarabine.

Patients are evaluated at 4-6 weeks.

PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic melanoma
• Measurable disease
• Resected or stable brain metastases are allowed

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Eastern Cooperative Oncology Group (ECOG) 0-1

Life expectancy

• At least 3 months

Hematopoietic

• See Immunologic
• Absolute neutrophil count > 1,000/mm^3 (without support of filgrastim [G-CSF])
• Platelet count > 100,000/mm^3
• Hemoglobin ≥ 8 g/dL (transfusion allowed)
• No coagulation disorders

Hepatic

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 times upper limit of normal
• Bilirubin ≤ 2 mg/dL (< 3 mg/dL in patients with Gilbert's syndrome)
• No hepatitis B or C

Renal

• Creatinine ≤ 1.6 mg/dL

Cardiovascular

• Left ventricular ejection fraction (LVEF) ≥ 45% by cardiac stress test*
• No active major cardiovascular illness as evidenced by stress thallium or other comparable test
• No myocardial infarction
• No cardiac arrhythmias NOTE: *For patients ≥ 50 years of age receiving high-dose interleukin-2 (IL-2) OR patients with a history of electrocardiogram (EKG) abnormalities, symptoms of cardiac ischemia, or arrhythmias

Pulmonary

• Forced expiratory volume 1 (FEV_1) ≥ 60% of predicted by pulmonary function test in patients with prolonged history of cigarette smoking or symptoms of respiratory dysfunction*
• No active major respiratory illness
• No obstructive or restrictive pulmonary disease NOTE: *For patients receiving high-dose IL-2 only

Immunologic

• No active major immunologic illness
• No active systemic infections
• No primary or secondary immunodeficiency

• Fully recovered immune competence after prior chemotherapy or radiotherapy as evidenced by both of the following:

• Absolute neutrophil count > 1,000/mm^3
• No opportunistic infections
• Human Immunodeficiency virus (HIV) negative
• Epstein-Barr virus positive

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 4 months after study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• At least 6 weeks since prior nitrosourea therapy
• No prior cyclophosphamide and fludarabine as part of a preparative regimen on National Cancer Institute (NCI) Surgery Branch adoptive cell therapy studies unless sufficient numbers of CD34+ stem cells (more than 2 x10^6/kg patient weight) have been obtained prior to the administration of chemotherapy

Endocrine therapy

• No concurrent systemic steroid therapy

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics
• Prior minor surgery within the past 3 weeks allowed if recovered

Other

• Recovered from all prior therapy
• At least 30 days since prior systemic therapy
• No other concurrent experimental agents