The primary objective is to determine the maximum tolerated hypofractionated radiotherapy dose (MTD) to a solitary metastatic focus ('index lesion') when followed by ipilimumab, in metastatic melanoma patients without brain involvement The secondary objectives are to determine late toxicity, immune-related clinical responses and immune pharmacodynamic changes after hypofractionated radiotherapy followed by ipilimumab

Inclusion Criteria

• Patient > 18 years old
• Histologically confirmed diagnosis of melanoma
• Previously treated or previously untreated metastatic melanoma by AJCC staging criteria
• Presence of an index lesion > 1 cm amenable to hypofractionated radiotherapy and at least one other additional lesion that can be followed for response using RECIST criteria
• ECOG Performance status 0 or 1
• Signed informed consent document
• Ability to tolerate stereotactic body radiation therapy (e.g. lie flat and hold position for treatment)

Exclusion Criteria

• Prior systemic therapy within 14 days of study enrollment. Patients must be adequately recovered from prior systemic therapy side effects as deemed by the PI.
• Clinical contraindication to stereotactic body radiotherapy (e.g. active systemic sclerosis, active inflammatory bowel disease if bowel is within target field, etc)
• Presence or history of central nervous system metastasis (including brain)
• Long-term use of systemic corticosteroids
• Prior RT that precludes the delivery of hypofractionated radiotherapy