Vaccine Therapy and Autologous Lymphocyte Infusion With or Without Fludarabine in Treating Patients With Metastatic Melanoma

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-α, interleukin (IL)-6, IL-1β, 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.