• Disease control rate at 24 weeks as defined by the immune-related Response Criteria (irRC) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  Disease control rate will be measured at 24 weeks from the start date of protocol therapy using the immune-related Response Criteria (irRC)
  
  

• Assessment of immune activation as determined in the Companion Protocol [ Time Frame: Three years ] [ Designated as safety issue: No ]
  Blood will be drawn for immunologic testing at each patient visit.
  
  
• Duration of disease control defined as the time from the date of the first treatment dose to the date of first documentation of disease progression as defined by irRC. [ Time Frame: Four years ] [ Designated as safety issue: No ]
  According to irRC criteria, increase in the size of target lesions or the appearance of new lesions within 12 weeks of the initiation of ipilimumab therapy does not necessarily represent disease progression (as they would using conventional RECIST criteria).
  
  
• Overall Survival (OS) [ Time Frame: Four years ] [ Designated as safety issue: No ]
  Overall Survival (OS) is defined as the time from the date of the first treatment dose to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the patient was known to be alive.
  
  
• Objective Response Rate (RR) [ Time Frame: Two years ] [ Designated as safety issue: No ]
  The Objective Response Rate (RR) at any time during the 2 years of study treatment will be evaluated in this study using the immune related Response Criteria (irRC).
  
  
• Time to Objective response [ Time Frame: Three years ] [ Designated as safety issue: No ]
  The Time to Objective response is defined as the time from the date of the first treatment dose to the date of first documentation of disease response.
  
  
• Duration of objective response (CR or PR) [ Time Frame: Four years ] [ Designated as safety issue: No ]
  The duration of objective response (CR or PR) will be measured from the date the response was first documented to the date of progression or death due to progressive disease, whichever occurs first.
  
  
• Safety of the combination [ Time Frame: Three years ] [ Designated as safety issue: Yes ]
  The safety of the combination as defined by the NCI CTCAE criteria, Version 4.0.
  
  

Biological: Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on D1 of each 21-day cycle for 8 cycles until month 6. Maintenance therapy will begin at month 6 and will consist 14 days of GM-CSF repeated every 3 months for up to 2 years or until disease progression, whichever occurs first.
Other Names:
• Leukine
• Sargramostim
Biological: Ipilimumab
Patients will be treated with 4 courses of ipilimumab administered every 3 weeks intravenously in a dose of 10 mg/kg, with appropriate stopping/de-escalation rules. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose administered at the end of cycle 4 repeated every 3 months for up to 2 years or until disease progression, whichever occurs first.
Other Names:
• Yervoy
• Anti-CTLA-4 Monoclonal Antibody

The study is an open-label, single arm single Center Phase II study to evaluate the safety and efficacy of the combination of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF, Leukine) and Ipilimumab (Yervoy) as therapy for patients with unresectable metastatic malignant melanoma. The patient sample will be approximately 43 evaluable individuals, males and females 18 years of age or older with measurable metastatic melanoma. Immunologic testing will be done to evaluate correlation with clinical outcome.

Patients will be treated with 4 courses of GM-CSF and ipilimumab administered every 3 weeks. GM-CSF will be administered subcutaneously daily for 14 days in a dose of 125 µg/m2 beginning on D1 of each 21-day cycle. Ipilimumab intravenously in a dose of 10 mg/kg, with appropriate stopping/de-escalation rules. After the initial 3 months (4 cycles) of treatment, GM-CSF administration will continue for 4 additional cycles on the same schedule and dose without ipilimumab for 14 days every 21 days until month 6. Maintenance therapy will begin at month 6 and will consist of ipilimumab in the same dose administered at the end of cycle 4 combined with 14 days of GM-CSF. Administration of this combination will be repeated every 3 months for up to 2 years or until disease progression, whichever occurs first. During the maintenance phase, GM-CSF will only be administered for 14 days in conjunction with ipilimumab and will not be administered in the intervening time period.