Pilot Ipilimumab in Stage IV Melanoma Receiving Palliative Radiation Therapy

Inclusion Criteria: 1. Signed Written Informed Consent Before any study procedures are performed, subjects (or their legally acceptable representatives) will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel. 2. Target Population * Histologically confirmed Stage IV melanoma. * Must have failed at least one systemic therapy for malignant melanoma or be intolerant to at least one prior systemic treatment. * Subjects with asymptomatic brain metastases are eligible. (Systemic steroids should be avoided if possible, or the subject should be stable on the lowest clinically effective dose, as steroids as they may interfere with the activity of ipilimumab if administered at the time of the first ipilimumab dose.) * Primary ocular and mucosal melanomas are allowed. * Must be at least 28 days since treatment with chemotherapy, biochemotherapy, surgery, radiation, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * Life expectancy of ≥ 16 weeks. * Subjects must have baseline (screening/baseline) radiographic images, (e.g. brain, chest, abdomen, pelvis, and bone scans with specific imaging tests to be determined by the attending physician) within 6 weeks of initiation of ipilimumab. * Required values for initial laboratory tests: * White blood cell (WBC) ≥ 2000/uL (\~ 2 x 10\^9/L) * Absolute neutrophil count (ANC) ≥ 1000/uL (\~ 1 x 10\^9/L) * Platelets ≥ 75 x 10\^3/uL (\~ 75 x 10\^9/L) * Hemoglobin ≥ 9 g/dL (\~ 80 g/L; may be transfused) * Creatinine \~ 2 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) \~ 2.5 x ULN for subjects without liver metastasis \~ 5 times for liver metastases * Bilirubin: \~ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must have a total bilirubin of \< 3.0 mg/dL) * No active or chronic infection with HIV, Hepatitis B, or Hepatitis C. * Two or more measurable sites of disease (≥ 1.5 cm) which include the disease site that requires palliative radiation therapy as well as ≥ 1 other disease site outside of the planned radiation therapy field. 3. Age and Sex * Men and women, at least 18 years of age. * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study \[and for up to 26 weeks after the last dose of investigational product\] in such a manner that the risk of pregnancy is minimized. * WOCBP include any female who has experienced menarche and who has undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as: * Amenorrhea ≥ 12 consecutive months without another cause, or * For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL * Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. c) Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study \[and for up to 26 weeks after the last dose of investigational product\] in such a manner that the risk of pregnancy is minimized. Exclusion Criteria: 1. Sex and Reproductive Status * WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 8 weeks after the last dose of investigational product. * WOCBP using a prohibited contraceptive method. * Women who are pregnant or breastfeeding. * Women with a positive pregnancy test on enrollment or before investigational product administration. 2. Target Disease Exceptions * Subjects on any other systemic therapy for cancer, including any other experimental treatment. * Prior treatment with an anti-CTLA-4 antibody if treatment failure was due to adverse events (AEs). If a subject was discontinued from the prior anti-CTLA-4 treatment due to an AE or serious adverse event (SAE), regardless of the type of event, that discontinuation constitutes an exclusion criterion. If AEs were serious enough to require a subject's withdrawal from prior treatment, the subject should be excluded from this study. * A history of AEs with prior IL-2 or Interferon will not preclude subjects from entering the current study. * Subjects who relapsed in study MDX010-16 are not eligible for this study. 3. Medical History and Concurrent Diseases * Autoimmune disease: subjects with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are subjects with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\]; systemic lupus erythematosus (SLE); autoimmune vasculitis \[eg, Wegener's Granulomatosis\]). Subjects with motor neuropathy considered of autoimmune origin (eg, Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from this study. * Any subject who has a life-threatening condition that requires high-dose immunosuppressant(s) * Presence of known Hepatitis B or Hepatitis C infection, regardless of control on antiviral therapy * Subjects with melanoma who have another active, concurrent, malignant disease are not eligible for the CA184045 study, with the exception of subjects with adequately treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix. 4. Medical History and Concurrent Diseases * Prisoners or subjects who are involuntarily incarcerated. * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. * Any underlying medical or psychiatric condition that, in the opinion of the investigator, could make the administration of ipilimumab hazardous or could obscure the interpretation of adverse events. * Any non-oncology vaccine therapy used for prevention of infectious diseases for up to 4 weeks before or after any dose of ipilimumab, with the exceptions of amantadine and flumadine. * Central nervous system (CNS) metastases that require palliative radiation therapy; prior brain irradiation is allowed providing CNS disease is stable. 5. Additional Concomitant Treatments * Any investigational agents * Any other (non-CA184045 related) CTLA-4 inhibitors or agonists * CD137 agonists * Immunosuppressive agents (unless required for treating potential AEs) * Chronic systemic corticosteroids (unless required for treating treatment emergent AEs or required for management of signs or symptoms due to brain metastases, upon discussion with BMS medical monitor). Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.