vaccine therapy using melanoma peptides for cytotoxic t cells and helper t cells in treating patients with metastatic melanoma

Conditions: Melanoma (Skin)

Summary: rationale: vaccines made from peptides may make the body build an immune response to kill tumor cells. purpose: this randomized phase ii trial is studying four different vaccines using melanoma peptides from cytotoxic t cells and helper t cells to see how well they work in treating patients with metastatic melanoma.

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.

Eligibility criteria:
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

Keywords: stage iv melanoma recurrent melanoma