Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease

PRIMARY OBJECTIVES:

I. To determine the safety and/or recommended dose of intrathecal (IT) nivolumab in
combination with systemic nivolumab treatment in patients with leptomeningeal disease (LMD).

SECONDARY OBJECTIVES:

I. To assess overall survival with combined intrathecal and systemic administration of
nivolumab in this patient population.

EXPLORATORY OBJECTIVES:

I. Compare the immunological effects of this treatment on immune cells in the cerebrospinal
fluid (CSF) to those observed in the peripheral blood and in non-LMD tumors.

II. Evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety
of this regimen.

III. To assess the effect of nivolumab on subsequent treatment. IV. To compare levels of
nivolumab in the CSF and peripheral blood.

OUTLINE: This is a phase I, dose-escalation study followed by a phase Ib study.

Patients receive nivolumab IT over 5 minutes on day 1. Beginning in course 2, patients also
receive nivolumab intravenously (IV) over 30 minutes on day 2. Courses repeat every 14 days
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Inclusion Criteria:

- Patients must have radiographic and/or CSF cytological evidence of LMD

- Must have a confirmed diagnosis of primary central nervous system (CNS) melanoma,
melanocytomas or metastatic melanoma (cutaneous, acral-lentiginous, uveal and mucosal
in origin), based on histological analysis of metastatic tissue and/or cancer cells,
archival tissue permitted

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
(PS) of =< 2

- Patients may receive steroids to control symptoms related to CNS involvement, but the
dose must be =< 4 mg per 24 hours of dexamethasone (or the equivalent). Patient's
symptoms should experience stability of neurological symptoms for at least 7 days, or
on tapering dose of steroids. Physiologic replacement doses for adrenal insufficiency
is allowed on this protocol

- Patients who have received radiation to brain and/or spine, including whole brain
radiation, stereotactic radiosurgery, or stereotactic body radiation therapy (SBRT),
are eligible, but must have completed radiation treatment at least 7 days prior to the
start of treatment

- Concurrent treatment with other anti-cancer systemic therapies is not allowed. No
other concomitant intrathecal therapy with another agent will be allowed. For patients
that have received other systemic therapies, the minimum wash out period is as
follows:

- Patients that received previous IT therapy must have received their last
treatment >= 7 days prior to the start of treatment

- Patients who have received systemic chemotherapy must have received their last
treatment >= 21 days prior to the start of treatment

- Patients who have received an approved biologic therapy (e.g. anti-PD-1,
anti-CTLA4, IL2, interferon) must have received their last treatment >= 4 weeks
prior to the start of treatment

- Patients who have been treated with an approved targeted therapy (BRAF inhibitor
and/or MEK inhibitor) must have received their last treatment >= 7 days or 5
half-lives (whichever is shorter) prior to the start of treatment

- Patients who have received any other investigational agents must have received
their last treatment >= 14 days prior to the start of treatment

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form

- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

- Hemoglobin >= 9.0 g/dL

- Platelets >= 75 X 10^9/L

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.5 X upper limit of normal (ULN)

- Total bilirubin: =< 1.5 X ULN (isolated bilirubin > 1.5 X ULN is acceptable if
bilirubin is fractionated and direct bilirubin < 35%)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN

- Albumin >= 2.5 g/dL

- Creatinine OR =< 2 x ULN; calculated creatinine clearance OR >= 50 mL/min; 24-hour
urine creatinine clearance >= 50 mL/min

- Absence of contraindication for Ommaya reservoir

Exclusion Criteria:

- Patients must not have active autoimmune disease that has required systemic treatment
in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
4 mg daily dexamethasone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease

- Patients who have previously received a-PD-1 and/or anti-CTLA-4 will be eligible,
unless they have ongoing > grade 2 adverse event (AE) side effects of such therapy.
Ongoing physiologic replacement doses for adrenal and thyroid insufficiency are
allowed on protocol

- Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
biologic therapy) or investigational anti-cancer drug

- Pregnant or lactating female

- Subjects with major medical, neurologic or psychiatric condition who are judged as
unable to fully comply with study therapy or assessments should not be enrolled

- Patients with a history of pneumonitis

- Evidence of active infections =< 7 days prior to initiation of study drug therapy
(does not apply to viral infections that are presumed to be associated with the
underlying tumor type required for study entry)

- Use of non-oncology vaccines containing live virus for prevention of infectious
diseases within 12 weeks prior to study drug

- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on
antiretroviral therapy (ART)—due to the unknown effects of HIV on the immune response
to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs
in patients with HIV

- History of allergy to study drug components

- History of severe hypersensitivity reaction to any monoclonal antibody

- Prisoners or subjects who are involuntarily incarcerated

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness