Prospective Evaluation Of High-Dose Systemic Methotrexate In Patients With Breast Cancer And Leptomeningeal Metastasis

BACKGROUND:

Management of LMD in patients with metastatic breast cancer is an area of unmet clinical
need. Increased survival in the era of hormonal and HER2 directed therapies has further
heightened the need for more effective therapies against the late complications of metastatic
disease. Prognosis is dismal with median survivals ranging from 6-8 weeks in untreated
patients and with little improvement having been demonstrated over the past 20 years.

Recently, there has been renewed interest in systemic chemotherapeutic options in these
patients. Incorporation of systemic therapies into standard treatment algorithms has been
limited as many agents have not been shown to adequately penetrate the blood brain barrier.
High-dose methotrexate (HD-MTX), however, is unique in that it does penetrate the blood brain
barrier. In fact, evidence suggests that it may target areas of poor cerebrospinal fluid
(CSF) flow, penetrate bulk disease, and provide treatment to systemic disease burden.
Methotrexate is a drug known to have activity against breast cancer and has been used in
combination with cyclophosphamide and 5-fluorouracil as part of a standard adjuvant treatment
regimen.

Currently, HD-MTX is included in the NCCN Guidelines for LMD and is used intermittently at
Johns Hopkins and cancer centers across the nation for LMD in breast cancer. These
recommendations, however, are more representative of the lack of available therapies for LMD
as opposed to strong evidence-based data. Only two retrospective studies have suggested that
HD-MTX may be an effective option for treating central nervous system (CNS) metastasis, both
with substantial methodological limitations.

STUDY OBJECTIVE This phase II, prospective study will evaluate systemic, intravenous
high-dose methotrexate (HD-MTX) in breast cancer patients with leptomeningeal metastasis
(LMD). The primary objective is to determine if treatment with systemic intravenous HD-MTX
will result in an overall survival (OS) exceeding 12 weeks among patients with triple
negative, HER2-positive, and hormone refractory metastatic breast cancer patients with LMD
with and without parenchymal brain involvement.

Inclusion Criteria:

- Adults (male and female) age >18

- Eastern Cooperative Group (ECOG) Performance Scale 0-1 (see Appendix I)

- Histologically or cytologically confirmed invasive breast cancer of the following
subtype:

- TRIPLE NEGATIVE (ER-negative, PR-negative, and HER2-negative disease). Triple-negative
patients will be defined per ASCO-CAP Guidelines (American Society of Clinical
Oncology-College of American Pathologists).

- HER2-POSITIVE: HER2-positive patients will be defined per ASCO-CAP Guidelines.

- HORMONE REFRACTORY: Patients with ER/PR-positive disease according to ASCO-CAP
guidelines above may be considered if they have disease progression after two lines of
hormonal therapy (administered in the adjuvant or metastatic setting), or are deemed
clinically hormone-resistant taking into consideration the rate of progression of
disease or a short interval of time on first line hormonal therapy before progression.
Clinically hormone-resistant patients MUST also be discussed with the Study Chair,
Study co-Chair or designee in advance for approval.

NOTE: ASCO-CAP guidelines state that ER and PR assays be considered positive if there are
at least 1% positive tumor nuclei in the sample on testing in the presence of expected
reactivity of internal (normal epithelial elements) and external controls. HER2-positive is
defined as HER2 IHC 3+, ISH ≥ 2.0, or average HER2 copy number ≥ 6.0 signals.

NOTE: A patient who has a change in receptor status (e.g. PR negative to positive) may be
stratified as triple negative or hormone positive, contrary to the most recent receptor
testing, for the purposes of the study, based upon the clinical course at the discretion of
the Study Chair, Study co-Chair, or designee in advance for approval.

- Cytologic or unequivocal radiographic confirmation of leptomeningeal metastasis by
dural puncture and/or neuroimaging with or without known brain metastasis

- Adequate organ function as follows:

- Estimated creatinine clearance >70 cc/min (calculated by Cockcroft-Gault formula)

- White blood cell counts >3000 cells/mcL

- Absolute neutrophil count >1500 cells/mcL

- Platelet count >100,000 cells/mcL

- Hematocrit >30%

- Serum bilirubin <1.5 x the ULN

- Alanine aminotransferase or aspartate aminotransferase <2.5x the ULN

- Alkaline phosphatase <2.5x the ULN or <5x the ULN if secondary to liver metastasis

- Able to provide confirmed consent

Exclusion Criteria:

- Prior allergy or adverse reaction to methotrexate

- New York Heart Association Heart Failure Class >3 (see Appendix II)

- Active diabetes insipidus

- Active mucositis

- Chemotherapy or stereotactic radiotherapy within the last 2 weeks

- Whole brain radiotherapy within the last 6 months

- Prior treatment with any methotrexate containing systemic regimen within 1 year
(excluding intrathecal methotrexate)

- Concurrent or planned systemic chemotherapy, radiotherapy, new hormonal or anti-HER2
directed therapy directed at management of breast cancer (existing anti-HER2 therapy
can be continued as recently recommended in the National Consensus Guidelines

- Uncontrolled or progressive systemic disease or other concurrent condition which in
the Investigator's opinion makes HD-MTX an undesirable treatment option for the
patient or would jeopardize compliance

- Contraindication to MRI

- Use of salicylates, non-steroidal anti-inflammatory drugs, or sulfonamide medications
within one week of start of methotrexate

- Pregnant women or women who are breastfeeding.

- Patients with significant visceral fluid collections including ascites, pericardial
effusions, pleural effusions or others may experience delayed clearance of
methotrexate because of third space accumulation which could result in methotrexate
toxicity and inability tolerate the proposed study treatment. While these are not
absolute exclusions the Study Chair or co-Chairs should be contacted to discuss
possible enrollment. Patients with significant ascites defined as European Association
for the Study of the Liver > grade 2, or with asymptomatic pleural effusions with an
estimated size >200 mL, or with symptomatic pleural effusion of any size will be
excluded.