OBJECTIVES: * Compare the cytotoxic T-cell response to each of 12 melanoma peptides restricted by Human Leukocyte Antigen (HLA)-A1, -A2, or -A3 in patients with metastatic melanoma vaccinated with or without these 12 melanoma peptides and with or without helper peptides. * Compare the helper T-cell response to each of 6 melanoma helper peptides restricted by HLA-DR molecules in patients treated with these vaccinations. * Determine whether the addition of 6 melanoma helper peptides to a vaccine containing multiple class I Major histocompatibility complex (MHC)-restricted peptides augments T-cell responses to the class I restricted peptides in these patients. * Determine, preliminarily, whether booster vaccination maintains immune response in patients treated with these vaccinations. * Compare the rates of clinical response and survival in patients treated with these vaccinations. * Determine, preliminarily, whether cellular immune response correlates with clinical response and survival rates in patients treated with these vaccinations. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to HLA type (HLA-A1 vs HLA-A2 vs HLA-A1 and -A2 vs HLA-A3) and planned sentinel immunized node biopsy (yes vs no). Patients are randomized to 1 of 4 treatment arms. * Arm I: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (Granulocyte-macrophage colony-stimulating factor, GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. * Arm II: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. * Arm III (closed to accrual as of 5/19/08): Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. * Arm IV: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. In all arms, patients continue therapy in the absence of unacceptable toxicity or disease progression necessitating other urgent therapy. Patients are evaluated at 8 and 12 weeks. Beginning 2-3 weeks after the week-12 evaluation, patients with no evidence of disease progression may receive booster vaccinations according to their randomized treatment arm. Patients receive booster vaccination ID and SC once weekly for 3 weeks. Treatment repeats every 9 weeks for 1 course, every 12 weeks for 2 courses, and then every 24 weeks for 2 courses OR for up to 2 years (whichever comes first) provided the patient does not require an urgent change in therapy. After completion of study treatment, patients are followed every 6 months for 2 years and then for survival for 5 years from study randomization. ACTUAL ACCRUAL: A total of 175 patients were accrued for this study during March 2005 and January 2009.
Inclusion Criteria: * Histologically confirmed stage IV melanoma * Multiple primary melanomas allowed * Metastasis may be from a cutaneous, mucosal, ocular, or unknown primary site * Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST criteria) * Must have 2 extremities uninvolved with tumor * Must have at least 2 intact (undissected) axillary and/or inguinal lymph node basins * Prior sentinel node biopsy may not have violated the integrity of a nodal basin * This extremity may still be considered for vaccination * Human Lymphocyte Antigen (HLA)-A1, -A2, or -A3 positive * Prior brain metastases allowed provided all of the following are true: * Surgically resected or treated with gamma-knife or stereotactic radiosurgery * No disease progression in the brain for the past 3 months * More than 30 days since prior steroids for the management of brain metastases * Age: 18 and over * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Adequate organ function measured within 4 weeks before randomization: * White blood cell (WBC) at least 4,000/mm\^3 * Platelet count at least 100,000/mm\^3 * Lymphocyte count at least 700/mm\^3 * Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) no greater than 2 times upper limit of normal (ULN) * Bilirubin no greater than 2 times ULN * Alkaline phosphatase no greater than 2 times ULN * Lactic dehydrogenase no greater than 2 times ULN * Creatinine no greater than 1.8 mg/dL * Negative pregnancy test * Fertile patients must use effective contraception * No other malignancy within the past 5 years except nonmetastatic squamous cell or basal cell skin cancer, ductal or lobular carcinoma in situ of the breast, or carcinoma in situ of the cervix * At least 4 weeks since prior sargramostim (GM-CSF), interferon alfa-2b, or interleukin-2 * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) * More than 30 days since prior systemic corticosteroids, including any of the following: * Therapeutic doses of oral steroids (e.g., prednisone or dexamethasone) * Steroid inhalers (e.g., Advair) * Topical steroids and nasal steroids with low systemic absorption (e.g., fluticasone) or steroids with low systemic absorption (e.g., triamcinolone hexacetonide) injected into a joint space allowed * At least 4 weeks since prior local control or palliative radiotherapy and recovered * Recovered from prior major surgery Exclusion criteria: * More than 3 brain metastases * Metastatic lesions greater than 2 cm * Concurrent radiotherapy * Prior radiotherapy to measurable disease * Concurrent surgery * Concurrent corticosteroids * Concurrent topical or systemic steroids * Concurrent chemotherapy * Prior vaccination with any of the study peptides * Recent (within the past year) or concurrent addiction to alcohol or illicit drugs * Pregnant or nursing * Known or suspected major allergy to any components of the study vaccine * Significant detectable infection * Immunosuppression conditions * Prior or active autoimmune disorder requiring cytotoxic or mmunosuppressive therapy, except for any of the following: * Presence of laboratory evidence of autoimmune disease (e.g., positive antinuclear antibody (ANA) titer) without symptoms * Clinical evidence of vitiligo or other forms of depigmenting illness * Mild arthritis requiring nonsteroidal anti-inflammatory medication * Autoimmune disorder with visceral involvement
are designated in this study