Phase II Study of the Combination of High-dose Methotrexate and Intrathecal Liposomal Cytarabine in Patients With Leptomeningeal Metastases With or Without Parenchymal Brain Involvement

Inclusion Criteria:

- Women who are not pregnant (contraception must be used throughout the study)

- Diagnosis of breast cancer with metastases to CNS (regardless of receptor status),
leptomeningeal disease must be present with/without parenchymal brain involvement

- Ability to provide informed consent

- No prior treatment with whole brain radiotherapy (WBRT)

- If patient received stereotactic radiosurgery (SRS) prior to enrollment it must be
well documented which lesions were treated and index lesions (untreated) for follow
up must be identified, no treatment with SRS will be permitted while on the study

- CNS disease must be documented by magnetic resonance imaging (MRI) and cerebrospinal
fluid (CSF) cytology

- Karnofsky Performance Status > 60

- White blood cells (WBC) > 3.0 K

- Absolute neutrophil count (ANC) > 1.5 K

- Platelets (PLT) > 100 K

- Hematocrit (HCT) > 30%

- Acceptable renal function (glomerular filtration rate [GFR] >= 60 mL/min)

- Acceptable liver function (see exclusion criteria)

- Well controlled systemic disease

- Therapy for systemic disease allowing for addition of systemic HD-MTX and IT Depocyt
(in general patients receiving trastuzumab or lapatinib at the time of enrollment
will be allowed to continue); bisphosphonates (i.e., zoledronic acid) and denosumab
will be allowed; other non-CNS active chemotherapies might be allowed if no known
interactions with study drugs are present; this will be reviewed on case-by-case
basis

- Mini-mental status examination score of 24 or above

Exclusion Criteria:

- Serum bilirubin > 1.5 x the upper limit of reference range (ULRR)

- Serum creatinine > 1.5 x ULRR or creatinine clearance =< 60 mL/minute (calculated by
Cockcroft-Gault formula)

- Potassium, < 3.7 mmol/L despite supplementation; serum calcium (ionized or adjusted
for albumin,) or magnesium out of normal range despite supplementation

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULRR

- Alkaline phosphatase (ALP) > 2.5 x ULRR or > 5x ULRR if judged by the investigator to
be related to liver metastases

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it undesirable for the patient to participate in
the trial or which would jeopardize compliance with the protocol

- Patients with known pleural effusion or ascites

- Prior treatment with whole brain radiotherapy, prior treatment with stereotactic
radiosurgery (SRS) is allowed under conditions provided in the inclusion criteria

- Previous allergic or adverse reaction to methotrexate or cytarabine

- Prior treatment with systemic HD-MTX or IT liposomal cytarabine

- Prior IT therapy of any kind

- Women who are currently pregnant or breast feeding

- Previous or current malignancies of other histologies within the last 5 years, with
the exception of cervical carcinoma in situ and adequately treated basal cell or
squamous cell carcinoma of the skin

- Receipt of any investigational agents within 30 days prior to commencing study
treatment

- Last dose of prior chemotherapy discontinued less than 4 weeks before the start of
study therapy; patients who had no toxicities with prior chemotherapy can start study
treatment earlier than 4 weeks

- Last radiation therapy to the brain in the form of SRS within the last 2 weeks before
the start of study therapy

- Any unresolved toxicity greater than Common Toxicity Criteria (CTC) grade 1 from
previous anti-cancer therapy

- Previous enrollment in the present study

- Major surgery within 4 weeks prior to starting therapy, Ommaya reservoir can be used
for introduction of chemotherapy within 48-72 hours after placement