Improved Therapy Response Assessment in Metastatic Brain Tumors

Inclusion Criteria: * Participants must have histologically - or - radiographically confirmed metastatic disease from a primary non-small-cell lung cancer - or - metastatic melanoma. * Participants must have measurable disease in the central nervous system (CNS), defined as at least one lesion that can be accurately measured in at least one dimension as ≥5 mm with MRI - or - compromise more than 30 image voxels on perfusion MRI to ensure adequate parametric statistical assessments. For a perfusion MRI resolution of 1.2x1.2x5mm, this equals a tumor volume of 0.2cubic centimeters (cc). * Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥60%) * Life expectancy of greater than 6 weeks * Eligible for stereotactic radiosurgery * Have normal organ functions per clinical guidelines * Ability to understand and the willingness to sign a written informed consent document. * Previously untreated asymptomatic brain metastases - or - progressive brain metastases after systemic therapy or prior local therapy such as radiation or surgery as defined by: 1. Untreated measurable lesions in patients that have received surgery and/or SRS to one or more other lesions 2. Residual or progressive lesions after surgery if asymptomatic 3. Patients who have had prior whole-brain radiation therapy (WBRT) and/or SRS and then whose lesions have progressed are eligible. Lesions treated with SRS may be eligible if there is unequivocal evidence of progression 4. Progression after prior systemic therapy. Exclusion Criteria: * Participants who received major surgery must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. * Has a diagnosis of immunodeficiency or hypersensitivity to ipilimumab or any of its excipients (Cohorts C and D). * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. * Has a known additional malignancy that is progressing or requires active treatment. * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Unable to undergo brain MRI