• Overall survival [ Designated as safety issue: No ]
  
• Progression-free survival [ Designated as safety issue: No ]
  
• Time to progression [ Designated as safety issue: No ]
  

• Immunological response in patients receiving MART-1/gp100/tyrosinase/NY-ESO-1 with fludarabine [ Designated as safety issue: No ]
  
• Toxicity of MART-1/gp100/tyrosinase/NY-ESO-1 with fludarabine [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Assess the toxicity and immune responses in HLA-A*0201-positive patients with chemotherapy-naïve metastatic melanoma treated with either escalating doses of fludarabine or no fludarabine followed by autologous lymphocyte infusion and vaccination with dendritic cells matured ex vivo with a cytokine cocktail and pulsed with MART-1/gp100/tyrosinase/NY-ESO-1/MAGE-3 class I and II peptides.

Secondary

• Compare clinical responses in patients receiving these regimens.

OUTLINE: This is a randomized, controlled, multicenter, dose-escalation study of fludarabine. Patients are randomized to 1 of 2 treatment arms.

All patients undergo two apheresis procedures, one to collect lymphocytes for the autologous lymphocyte infusion and one to collect dendritic cells (DC) for the production of the autologous vaccine. Autologous DC are pulsed with tumor antigen class I and II peptides derived from MART-1, gp100, tyrosinase, NY-ESO-1, and MAGE-3 and matured with a cytokine cocktail comprising tumor necrosis factor-%u03B1, interleukin (IL)-6, IL-1%u03B2, and prostaglandin E2.

• Arm I: Patients receive fludarabine IV over 30 minutes on days -7 to -3 (beginning 3 days after the second apheresis procedure). Patients receive autologous lymphocyte infusion IV over 1 hour on day 0 followed by vaccination with autologous peptide-pulsed DC intranodally over 24 hours on days 1, 8, 22, and 36. Patients who have stable disease or who achieve a response to treatment may receive re-treatment with fludarabine, autologous lymphocyte infusion, and autologous peptide-pulsed DC vaccine (as above) approximately 4 weeks to 6 months after the last DC vaccine.

Cohorts of 3-12 patients receive escalating doses of fludarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 or 3 of 12 patients experience dose-limiting toxicity.

• Arm II: Patients receive autologous lymphocyte infusion and vaccination with autologous peptide-pulsed DC as in arm I. Patients who have stable disease or who achieve a response to treatment may receive re-treatment with autologous lymphocyte infusion and autologous peptide-pulsed DC vaccine (as in arm I) approximately 4 weeks to 6 months after the last DC vaccine.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of metastatic melanoma

  • The following subtypes are also eligible:

    • Unresectable stage III or IV uveal melanoma
    • Metastatic mucosal melanoma
• Measurable disease after attempted curative surgical therapy

• Tumor tissue must be available for immunohistochemical staining

  • Positive for %u2265 1 of the following peptides:

    • MART-1
    • Tyrosinase
    • NY-ESO-1
    • HMB-45
• HLA-A *0201 positive
• Positive for DR4 and/or DP4 by DNA SSOP analysis

PATIENT CHARACTERISTICS:

• ECOG performance status 0 or 1
• WBC %u2265 3,000/mm^3
• Hemoglobin %u2265 9.0 g/dL
• Platelet count %u2265 100,000/mm^3
• Bilirubin %u2264 2.0 mg/dL
• ALT/AST < 3 times upper limit of normal
• Creatinine %u2264 2.0 mg/dL
• Seropositive for Epstein-Barr virus
• No major systemic infections
• No coagulation disorders
• No documented myocardial infarction in the past 6 months
• No other major medical illnesses of the cardiovascular or respiratory systems
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known positivity for hepatitis B surface antigen or hepatitis C antibody
• No known HIV positivity
• No prior uveitis or autoimmune inflammatory eye disease
• No other malignancy except for cervical carcinoma in situ or basal cell or squamous cell skin cancer unless patient was curatively treated > 5 years ago and has no detectable disease

• No history of any of the following:

  • Hypogammaglobulinemia
  • Lymphocytopenia
  • Impaired immune response
  • Tuberculosis or positive PPD unless patient received prior bacilli Calmette-Guérin vaccine (BCG)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy
• Prior adjuvant interferon or isolated limb perfusion allowed
• More than 1 month since prior and no other concurrent therapy for melanoma, including radiotherapy, chemotherapy, or adjuvant therapy
• At least 1 month since prior surgery
• No concurrent steroid therapy
• No prior gp100 209-217 (210M), MART-1 26-35 (27L), gp100 280-288 (288V), tyrosinase 207-215, or NY-ESO-1 157-165 (165V) peptides