Inclusion Criteria:

• Patients must have a written informed consent obtained prior to the initiation of study procedures.
• Male and female subjects greater than or equal to 18 years of age.
• Patients must have histologically confirmed recurrent stage III or stage IV melanoma (AJCC 6th edition classification). Cutaneous melanoma, ocular or mucosal melanoma will be eligible.
• Patients must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Baseline measurements must be obtained within 4 weeks prior to initiating therapy.
• Patients must have adequate hematologic, renal, and liver function as evidenced by the following (within 4 weeks prior to starting the study drugs):
• WBC greater than or equal to 3,000/mm3
• Lymphocytes greater than or equal to 1,000/mm3
• Platelets greater than or equal to 100,000/mm3
• Serum Creatinine less than or equal to 1.5 x upper limit of normal (ULN)
• Serum Bilirubin less than or equal to 1.5 x ULN
• Serum AST/ALT less than or equal to 2.5 x ULN
• Serum LDH less than or equal to 2.0 x ULN
• APTT less than < 40 s
• Patients must have fully recovered from any effects of major surgery, and be free of significant detectable infection.
• Patients must not have received any chemotherapy, hormonal therapy, radiotherapy, or biological therapy within the preceding 4 weeks.
• Patients must not have previous therapy with Anti-CTLA4 monoclonal antibodies (including CP-675,206 and MDX-010). Previous therapy with Interferon-alfa 2b in the adjuvant or metastatic setting is allowed. Previous therapy with other biological agents (including vaccines and GM-CSF) is allowed.
• Patients must have ECOG performance status of 0 or 1.
• Patients must not have autoimmune disorders (except vitiligo). Patients with positive titers for autoimmune antibodies are allowed on the study in the absence of history of clinical manifestations of autoimmune disease.
• Patients must not have conditions of immunosuppression or chronic requirement for treatment with systemic steroids, including oral steroids, continuous use of topical steroid creams or ointments, or any inhaled steroid containing inhalers. Patients who discontinue use of these classes of medication for at least 2 weeks are eligible. Treatment with steroids or other immunosuppressant medications is allowed during the study if clinically required to treat side effects related to autoimmunity that may develop secondary to the study agents.
• Patients must be free of brain metastasis by contrast-enhanced CT/MRI scans within 4 weeks prior to starting the study drugs. If known to have prior brain metastases, must not have evidence of active brain disease on two successive MRI evaluations at least 3 months apart (one of which is £ 4 weeks prior to starting the study drugs).
• Female patients of child bearing potential must have a negative pregnancy test, and must not be breast feeding.
• Patients must agree to use effective contraception (both males and females).

Exclusion Criteria

• Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, hypertension, cardiac ischemia, myocardial infarction, severe cardiac arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or restrictive pulmonary diseases, active systemic infections, and inflammatory bowel disorders.
• Treatment with mitomycin C or nitrosureas within six weeks prior to study entry.
• Any significant psychiatric disease, medical intervention, or other condition, which in the opinion of the principal investigator, could prevent adequate informed consent or compromise participation in the clinical trial.
• Active infection or antibiotics within one-week prior to study, including unexplained fever (temp > 38.1°C).
• Treatment with anticoagulants, except to keep an indwelling line patent.
• Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study.
• Treatment with any investigational product within 28 days of registration.
• History of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), celiac disease, or other chronic gastrointestinal conditions associated with diarrhea, or current acute colitis of any origin, or any history of diverticulitis (even a single episode) or evidence of diverticulitis at baseline, including evidence limited to CT-scan only.
• Patients who did not tolerate high-dose interferon-α therapy in the adjuvant setting will be excluded.