Novel Adjuvants for Peptide-Based Melanoma Vaccines

An Open Label Study of MDX-CTLA4 in Combination With Tyrosinase/gp100/MART-1 Peptides Emulsified With Montanide ISA 51 in the Treatment of Patients With Resected Stage III or IV Melanoma

This is a study to determine the efficacy of a melanoma vaccine chemotherapy cocktail composed of CTLA-4 antibody; tyrosinase, gp100, and MART-1 peptides; and incomplete Freund's adjuvant (IFA) with or without interleukin-12 in patients with resected stage III or IV melanoma.

In the Phase I/II trial, patients with resected stages III and IV melanoma who have been rendered free of disease, but are at high risk of relapse, are treated with peptides/IFA at a dose of 0.5 mg each peptide plus CTLA-4 antibody given intravenously, 3 mg/kg, after each vaccination. In the Phase II randomized study, patients are treated with the melanoma peptide vaccine alone, with CTLA-4 antibody, or with CTLA-4 antibody combined with IL-12 at 30 ng/kg with alum. The peptides are tyrosinase 368-376 (370D); gp100 209-217 (210M); and MART-1 26-35 (27L) which are emulsified with IFA. The dosing schedule for both trials are at 1, 2, 3, 4, 5, and 6 months; then at 9 and 12 for a total of 8 vaccinations.

Inclusion criteria:

• Diagnosis of stage III or IV cutaneous, mucosal, or ocular melanoma
• Completely resected disease or disease-free
• HLA-A2.1 positive
• Tumor tissue available for immunohistochemical analysis and staining positive for at least 1 of the specified antigens
• At least 1 month since prior therapy for cancer, including radiotherapy and adjuvant therapy
• WBC count at least 3,000/mm3
• Granulocyte count at least 1,500/mm3
• Platelet count at least 100,000/mm3
• Hemoglobin at least 9.0 gm/dL
• Creatinine no greater than 2.0 mg/dL
• Bilirubin no greater than 2.0 mg/dL
• SGOT/SGPT no greater than 2.5 times upper limit of normal
• ECOG performance status 0-1
• Have failed alpha-interferons (patients with resected stage III disease)

Exclusion criteria:

• Prior treatment with tyrosinase: 368-376(370D), gp100:209-217(210M), and MART-1:26-35(27L) peptides
• Steroid therapy or other immunosuppressive medication requirement
• Major systemic infections (e.g., pneumonia or sepsis)
• Coagulation or bleeding disorders
• Major medical illnesses of the gastrointestinal, cardiovascular, or respiratory systems
• Allergic reaction to Montanide ISA 51 (incomplete Freund's adjuvant)
• History of uveitis or autoimmune inflammatory eye disease
• Other active autoimmune disease
• Positive for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody
• Pregnant or nursing