Ipilimumab Induction in Patients With Melanoma Brain Metastases Receiving Stereotactic Radiosurgery

This is a randomized Phase II selection study investigating the use of ipilimumab induction
prior to stereotactic radiosurgery (SRS), versus no induction, for melanoma brain metastases.
Participants will be randomized to Arm A "Induction" (two doses of ipilimumab prior to SRS,
two doses of ipilimumab after SRS) versus Arm B "No induction" (SRS first, followed by 4
doses of ipilimumab). Participants will undergo multiple dynamic contrast-enhanced MRIs of
the brain and submit blood samples for immune testing.

Inclusion Criteria:

- Patients with a histologically-confirmed diagnosis of melanoma who have imaging
findings suggestive of 1 to 4 brain metastases

- At least one lesion in the brain that is measurable, which is defined as ≥5 x 5mm
(Prior craniotomy and surgical resection is allowed, as long as there is at least one
remaining measurable lesion in the brain)

- Patients must be candidates for stereotactic radiosurgery (SRS) and planning to
undergo SRS

- Patients must be candidates for ipilimumab as determined by the treating physician

- Patients must be neurologically asymptomatic, or very minimally symptomatic, as judged
by the treating physicians

- At least 3 weeks has elapsed from any prior therapy, and the patient has recovered
from side effects to ≤ grade 1 toxicities per Common Terminology Criteria (CTC) for
Adverse Events

- Age > or = 18 years old

- Performance status of ECOG of 0 or 1 (ECOG is the Eastern Oncology Cooperative Group
Scoring system used to quantify cancer patients' general well-being and activities of
daily life; scores range from 0 to 5 where 0 is perfect health and 5 is death)

- Adequate organ and marrow function: alanine aminotransferase (ALT ) < 2.5x's upper
limit of normal (ULN) of the institutional normal reference range, aspartate
aminotransferase (AST) < 2.5x's ULN of the institutional normal reference range,
Bilirubin < 1.5x's ULN of the institutional normal reference range, Creatinine < 2.0
milligrams per deciliter, Platelets > 50,000 per microliter

- Women of child-bearing potential must agree to use adequate contraception, defined as
complete abstinence from intercourse with men or two methods

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Previous radiotherapy to the lesion(s) of interest, including prior treatment with
whole brain radiation therapy (WBRT). Prior treatment with SRS is allowed if the index
lesion(s) is in a different, non-contiguous location than the previously treated
lesion.

- Patients who have previously received ipilimumab, PD-1 inhibitors or PD-L1 inhibitors
are excluded due to the potential of effects on primary outcome

- Patients who require WBRT or surgery at the time of enrollment

- Neurologic symptoms or imaging findings that necessitate the use of steroids on the
day of enrollment or in the prior 7 days

- Highly suspicious magnetic resonance imaging (MRI) or cerebrospinal fluid evidence of
leptomeningeal metastases, unless all measurable disease is localized and SRS is
considered the treatment of choice

- Concurrent treatment with any other anti-neoplastic drug or concurrent participation
in another therapeutic clinical trial

- Patients unable to undergo or tolerate MRI scans (presence of cardiac pacemaker,
implanted cardiac defibrillator, aneurysm clips, history of allergic
reaction/hypersensitivity to gadolinium)

- Women who are pregnant or are nursing

- Patients with absolute lymphocyte count of <500 cells/microliter, who are known to be
HIV positive, who have clinically significant active autoimmune disease, or are
receiving immunosuppression following solid organ or stem cell transplant