Liposomal Cytarabine and High-Dose Methotrexate in Treating Patients With Central Nervous System Metastases From Breast Cancer

PRIMARY OBJECTIVES:

I. To show that treatment with high-dose methotrexate (HD-MTX) in combination with
intrathecal (IT) sustained-release cytarabine (liposomal cytarabine) will result in median
progression-free survival (PFS) greater than 7 weeks for patients with breast cancer and
leptomeningeal metastases with or without parenchymal brain involvement.

SECONDARY OBJECTIVES:

I. To describe the overall survival of patients with central nervous system (CNS) metastatic
breast cancer treated with the combination of intravenous (IV) HD-MTX and IT Depocyt
(liposomal cytarabine).

II. To describe the safety of the combination therapy, in terms of toxicity, adverse events,
and the need for dose reductions or schedule modification.

III. To estimate the best overall response rate achieved during treatment with IV HD-MTX and
IT Depocyt. Radiographic response will be measured by the Macdonald Criteria using imaging
(magnetic resonance imaging [MRI]), and cytologic response will be measured by cerebrospinal
fluid (CSF) cytology.

IV. To determine the number of treatment cycles needed to achieve radiographic and cytologic
response.

V. To describe response duration in patients who achieve at least partial radiographic
response and cytologic clearance.

VI. To define time to clinical progression as measured by Karnofsky performance status (KPS)
and neurological exam.

VII. To describe functional status and quality of life of patients, through clinical
evaluations of neurological status and patient-reported quality of life (QOL) measured by
the Functional Assessment of Chronic Illness Therapy (FACIT) brain and/or CNS
questionnaires.

VIII. To correlate response rates with the extent of patient's systemic disease and tumor
receptor status (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth
factor receptor 2 [Her2]/neu and/or breast cancer, early onset [BRCA] if applicable).

OUTLINE:

INDUCTION THERAPY (WEEKS 1-6): Patients liposomal cytarabine IT or via lumbar puncture (LP)
every 14 days beginning in week 1. Patients also receive high-dose methotrexate IV every 14
days beginning in week 2. Treatment repeats every 14 days for 3 courses in the absence of
disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY (WEEKS 7-11): Patients achieving complete response (CR), partial
response (PR), or stable disease (SD) and CSF negative for malignant cells receive liposomal
cytarabine IT or via LP beginning in week 7 and high-dose methotrexate IV beginning in week
8. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY (WEEKS 13-37): Patients achieving CR, PR, or SD and CSF negative for
malignant cells receive liposomal cytarabine IT or via LP every 4 weeks beginning in week 13
and high-dose methotrexate IV monthly beginning in week 15. Treatment with liposomal
cytarabine repeats every 4 weeks for up to 5 courses and treatment with high-dose
methotrexate repeats monthly for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

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

- Able 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 untreated index lesions for follow up must be identified; no
treatment with SRS will be permitted while on the study; CNS disease must be
documented by MRI and 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%

- Glomerular filtration rate (GFR) >= 60 mL/min

- Acceptable liver function (see exclusion criteria)

- Any ongoing therapy for systemic disease allows for the 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 must be reviewed and approved
by the primary investigator on a case-by-case basis

- Mini-mental state 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 > 5 x 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 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, IT liposomal cytarabine, or IT therapy of any
kind

- 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 was 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

- Stereotactic radiosurgery (SRS) less than 2 weeks before the start of study therapy

- Any unresolved toxicity greater than Common Terminology Criteria for Adverse Events
(CTCAE) grade 1 from previous anti-cancer therapy

- Previous enrollment in the present study

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