RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Biological therapies use different ways to stimulate the immune system and stop tumor cells from growing. Treating a patient's white blood cells with interleukin-2 may stimulate them to kill tumor cells.

PURPOSE: This phase II trial is studying how well giving chemotherapy together with biological therapy works in treating patients with metastatic melanoma that has not responded to previous therapy.

OBJECTIVES:

• Determine whether clinical tumor regression occurs in patients with metastatic melanoma treated with adoptive transfer of lymphocytes in combination with interleukin-2 (IL-2) after a nonmyeloablative but lymphocyte-depleting regimen comprising cyclophosphamide and fludarabine.
• Determine the safe dose level of IL-2, cyclophosphamide, and fludarabine in these patients. (Phase I closed to accrual effective 07/24/2001.)
• Determine the survival of patients treated with infused cells following this nonmyeloablative regimen.
• Evaluate the long-term immune status of patients treated with this nonmyeloablative regimen.
• Determine the clinical responses of patients treated with the nonmyeloablative regimen, infused cells, and IL-2 at the maximum tolerated dose.
• Determine the impact of administering infused cells without filgrastim (G-CSF) in a select cohort of patients. (Cohort closed to accrual as of 02/27/2003)

OUTLINE: This is a dose-escalation study of interleukin-2 (IL-2), cyclophosphamide, and fludarabine. Patients are stratified according to route of administration of cloned lymphocytes (IV vs intra-arterial).

Phase I (Closed to accrual effective 07/24/2001)

• Harvest: Peripheral blood lymphocytes and/or tumor infiltrating lymphocytes are harvested and activated in vitro with the gp100 antigen (gp100) or the MART-1 antigen (MART-1) and IL-2 over a period of 4-6 weeks.

• Nonmyeloablative preparative regimen and lymphocyte administration: Patients are assigned to 1 of 4 cohorts and receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to -1 with or without IL-2.

  • Cohorts 1 and 2: Patients receive the preparative regimen above with increasing doses of cyclophosphamide but no IL-2.
  • Cohort 3: Patients receive the preparative regimen above with the maximum tolerated dose (MTD) of cyclophosphamide (defined as that at which the absolute neutrophil count recovers by day 14 in at least 2 of 3 or 4 of 6 patients) followed by low-dose IL-2 IV over 15 minutes every 8 hours on days 1-5 for 6 weeks.
  • Cohort 4: Patients receive the preparative regimen above with the MTD of cyclophosphamide followed by high-dose IL-2 IV over 15 minutes every 8 hours on days 1-3.

All patients receive activated lymphocytes IV or intra-arterially over 20-30 minutes on day 0*. Patients with a predominant site of disease with an identifiable vascular supply to tumor(s) receive cells via intra-arterial infusion. Beginning 1-2 days after completion of lymphocyte infusion, some patients receive filgrastim (G-CSF) subcutaneously once daily until blood counts recover.

NOTE: *Day 0 is 1-4 days after completion of fludarabine administration.

• Immunization: Patients are immunized with a peptide emulsified in Montanide ISA-51 once daily for 5 days and then weekly times 3 beginning on day 0**, depending on lymphocyte reactivity.

  • Patients receiving gp100 reactive cells receive the gp100 peptide.
  • Patients receiving MART-1 reactive cells receive the MART-1 peptide.
  • Patients receiving gp100 and MART-1 reactive cells receive the MART-1 peptide.
  • Patients receiving cells that are not reactive to either peptide are not immunized.

NOTE: **Immunization occurs on the same day as lymphocyte infusion

Phase II

• Two cohorts of patients receive preparative regimen, cells (IV vs intra-arterially), and high-dose*** IL-2 as in phase I of the study. An additional cohort of patients receives this same regimen but without filgrastim (G-CSF) (Cohort closed to accrual as of 02/27/2003).

NOTE: ***Patients ineligible to receive high-dose IL-2 due to the presence of cardiovascular or respiratory system illness may receive low-dose IL-2 SC daily on days 0-4, 7-11, 14-18, 21-25, 28-32, and 35-39.

Patients are followed at 3-4 weeks.

PROJECTED ACCRUAL: A total of 250 patients will be accrued for this study. (Phase I closed to accrual effective 07/24/2001.)

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic melanoma that is refractory to therapy
• Evaluable disease

PATIENT CHARACTERISTICS:

Age

• 16 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count greater than 1,000/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 1.6 mg/dL (less than 3.0 mg/dL for patients with Gilbert's syndrome)
• AST/ALT less than 2 times upper limit of normal
• Hepatitis B surface antigen negative

Renal

• Creatinine no greater than 1.6 mg/dL

Cardiovascular

• No major medical illness of the cardiovascular system

Pulmonary

• No major medical illness of the respiratory system

Other

• No major medical illness of the immune system
• No active systemic infection
• HIV negative
• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 months after study participation
• Must sign a durable power of attorney

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No concurrent steroid therapy

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• More than 4 weeks since any prior therapy