Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma

Inclusion Criteria:

* Ability to understand and the willingness to sign a written informed consent document;
* Histologic diagnosis of locally unresectable, metastatic melanoma.
* Any BRAF status is permitted
* Any prior therapy is permitted except prior therapy with ipilimumab.
* Patients must have at least 2 distinct measurable metastatic sites, with one of at least 1 cm or larger in its largest diameter and may have additional non-measurable but established metastatic lesions (i.e. bone metastases).
* Patients must have adequate organ and marrow function as defined by initial laboratory tests:

  * WBC 2000/uL
  * ANC 1000/uL
  * Platelets 50 x 103/uL
  * Hemoglobin 8 g/dL
  * Creatinine 3.0 x ULN
  * AST/ALT 2.5 x ULN for patients without liver metastasis
  * Bilirubin 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL;
* Performance status ECOG 0-1 or Karnofsky \> 50%;
* Men and women, ages \> 18 year old of age;
* Life expectancy \> 3 months
* Stable brain metastases for at least 4 weeks and not steroid dependent;
* 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 study.

Exclusion Criteria:

* Patients having no lesions outside the field of radiation thus nullifying the ability to measure an abscopal effect;
* 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;
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug 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 one month prior to or after any dose of ipilimumab);
* Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids;
* Women who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 8 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding;
* Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 8 weeks after study drug is stopped;
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.