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

• Safety [ Designated as safety issue: Yes ]
  
• Survival [ Designated as safety issue: No ]
  
• Long-term immune status [ Designated as safety issue: No ]
  
• Clinical response [ Designated as safety issue: No ]
  
• Impact of administering infused cells without filgrastim (G-CSF) [ Designated as safety issue: No ]
  

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.)