Vaccine Therapy With or Without Biological Therapy in Treating Patients With Metastatic Melanoma

OBJECTIVES:

• Determine immune response of vaccination with melanoma associated antigens (MART-1:27-35, gp100:209-217 (210M), and tyrosinase:368-376 (370D)) on the number of peptide specific CD8+ T-cell precursors in HLA-A2 positive patients with metastatic melanoma.
• Determine the influence of sargramostim (GM-CSF) and/or interferon alfa-2b (IFN-A) on the immune responses of these patients and toxicity of this melanoma peptide vaccine.
• Determine any antitumor and anti-pigmentary response that may result from immunization against MART-1, gp100 and tyrosinase peptides, and determine the relationship between such clinical observations and immune responses against lineage antigens with or without GM-CSF and/or IFN-A.
• Compare the relapse free survival and overall survival of patients treated with melanoma peptide vaccine alone or in combination with GM-CSF and/or IFN-A.

OUTLINE: This is a randomized, multicenter study.

Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive multiepitope peptide (MEP) vaccine comprising MART-1:27-35, gp100:209-217 (210M), and tyrosinase:368-376 (370D) peptides. Each peptide is separately emulsified in Montanide ISA-51 and administered subcutaneously (SC) (for a total of 2 injections per peptide) on days 1 and 15.
• Arm II: Patients receive MEP vaccine as in arm I and sargramostim (GM-CSF) subcutaneously (SC) daily on days 1-14.
• Arm III: Patients receive MEP vaccine as in arm I and interferon alfa-2b SC three times a week.
• Arm IV: Patients receive MEP vaccine as in arm I, GM-CSF as in arm II, and interferon alfa-2b as in arm III.

Treatment continues every 4 weeks for a maximum of 13 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 92 patients (23 per arm) will be accrued for this study within 13-16 months.

DISEASE CHARACTERISTICS:

• Histologically proven stage IV melanoma
• Measurable disease

• At least 1 lesion must be a minimum of 1.0 cm in diameter
• Bone metastases are not considered to be measurable disease
• No prior radiotherapy to area of measurable disease unless there is clearly progressive disease in this site or measurable disease exists outside the area of prior radiotherapy
• HLA-A2 positive
• No brain disease by MRI or CT scan within 4 weeks prior to randomization

• Prior brain disease allowed if no evidence of active disease by 2 successive MRI evaluations completed at least 3 months apart

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 4,000/mm^3
• Platelet count at least 100,000/mm^3
• Lymphocyte count greater than 700/mm ^3

Hepatic:

• SGOT no greater than 2 times upper limit of normal (ULN)
• Bilirubin no greater than 2 times ULN
• Alkaline phosphatase and lactic dehydrogenase no greater than 2 times ULN

Renal:

• Creatinine no greater than 1.8 mg/dL

Other:

• No significant detectable infection
• HIV negative
• No other malignancy within the past 5 years except:

• Any carcinoma in situ
• Lobular carcinoma in situ of the breast
• Carcinoma in situ of the cervix
• Atypical melanocytic hyperplasia
• Melanoma in situ
• Basal cell or squamous cell skin cancer
• No autoimmune disorders or conditions of immunosuppression
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior MART-1:27-35, gp100:209-217 (210M), or tyrosinase:368-376 (370D) peptide
• Greater than 4 weeks since prior adjuvant immunotherapy, including sargramostim (GM-CSF) or interferon alfa-2b

Chemotherapy:

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy:

• At least 2 weeks since prior and no concurrent systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone); continuous use of topical steroid creams or ointments; or any inhalers containing steroids

Radiotherapy:

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy for local control or palliation and recovered

Surgery:

• Recovered from any prior major surgery