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Investigator(s):
Steven A. Rosenberg, M.D., Ph.D. Principal Investigator Phone: 1-866-820-4505 (Toll Free) ncisbirc@mail.nih.gov
Referral Contact(s):
June A. Kryk, R.N. Research Nurse Phone: 1-866-820-4505 (Toll Free) Fax: 301-451-1927 ncisbirc@mail.nih.gov	Linda Williams, R.N. Research Nurse Phone: 1-866-820-4505 (Toll Free) Fax: 301-451-1927 ncisbirc@mail.nih.gov

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Primary Eligibility:

• Must be > 16 years old, in good general health with histologically confirmed cutaneous metastatic melanoma; ocular or mucosal primary not eligible; must have at least one site of disease 1cm in size
• No active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system
• Lab values must be within acceptable limits: HGB ≥ 8.0 mg/dl, ANC ≥ 1000/ml, platelets ≥ 100,000 ml, ALT/AST < 2x upper limit of normal, serum creatinine < 1.6 mg/dl, total bilirubin ≤ 1.6 mg/dl
• Must be more than 4 weeks since previous systemic therapy or six weeks since nitrosurea therapy; patient must have recovered from any physical or hematological side effects from therapy

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Study 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.

*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

**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)

***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

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 6/29/09
Updated: 7/27/09