Study of Radiotherapy Administered in Combination With Ipilimumab in Patients With Unresectable Stage III or Stage IV Advanced Malignant Melanoma (Mel-Ipi-Rx)

Inclusion Criteria:

• Willing and able to give written informed consent.
• Histologic diagnosis of melanoma.
• Unresectable locally advanced or metastatic melanoma with at least one melanoma metastasis accessible to radiation therapy.
• Measurable disease according to immune related Response Criteria
• Required values for initial laboratory tests:

WBC >= 2000/uL ANC >= 1000/uL Platelets >= 75 x 103/uL Hemoglobin >= 8 g/dL Creatinine <= 2,5 x ULN AST/ALT <= 2.5 x ULN for patients without liver metastasis or <= 5 x ULN for patients with liver metastasis Total Bilirubin <= 1,5.x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
• ECOG Performance status of 0 or 1.
• Men and women, >= 18 years of age.
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Suspected or known CNS tumors including brain metastasis.
• Any other malignancy form which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
• Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
• Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
• Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
• A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist.
• Concomitant hormonal treatment, chemotherapy or immunotherapy.
• Other investigational therapy.
• Prior radiotherapy within the same body area.
• Prior radiotherapy targeting fields containing flat bones.
• Women of childbearing potential (WOCBP), defined above
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
• Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 8 weeks after ipilimumab is stopped.