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High-Dose Methotrexate in Treating Patients with Breast Cancer and Leptomeningeal Metastasis

Trial Status: Active

This phase II trial studies how well high-dose methotrexate works in treating patients with breast cancer that has spread to the thin layers of tissue that cover and protect the brain and spinal cord called leptomeninges (leptomeningeal metastasis). Drugs used in chemotherapy, such as methotrexate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Inclusion Criteria

  • Eastern Cooperative Group (ECOG) performance scale 0-1
  • Histologically or cytologically confirmed invasive breast cancer of the following subtype: * TRIPLE NEGATIVE (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative disease); triple-negative patients will be defined per American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines * 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 (Roisin Connolly, MBBCh), 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 immunohistochemistry (IHC) 3+, in situ hybridization (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 (Roisin Connolly, MBBCh), 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
  • 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 upper limit of normal (ULN) or < 5 x the ULN if secondary to liver metastasis
  • Alanine aminotransferase or aspartate aminotransferase < 2.5 x the ULN or < 5 x the ULN if secondary to liver metastasis
  • Alkaline phosphatase < 2.5 x the ULN or < 5 x the ULN if secondary to liver metastasis
  • Able to provide confirmed consent
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for six months following the conclusion of study participation; if a woman were to become pregnant she will be excluded from the study immediately

Exclusion Criteria

  • Prior allergy or adverse reaction to methotrexate
  • New York Heart Association heart failure class >= 3
  • Active diabetes insipidus
  • Active mucositis
  • Chemotherapy or stereotactic radiotherapy within the last 2 weeks
  • Partial brain radiotherapy (i.e. =< 40% of total brain volume) within the last 2 weeks
  • Whole brain radiotherapy within the last 6 months or partial brain radiotherapy exceeding > 40% of total brain volume 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 magnetic resonance imaging (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 to 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 * Systemic staging of the chest/abdomen (abd), pelvis is required for study entry; body fluid will be assessed based on this study


Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Stuart Alan Grossman


Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE
Contact: Jian Li Campian
Phone: 314-362-5677

North Carolina

Wake Forest University Health Sciences
Status: ACTIVE
Contact: Roy Ervin Strowd
Phone: 336-716-7548


I. To assess if treatment with systemic intravenous high-dose (HD)-methotrexate (MTX) will result in an overall survival (OS) exceeding 12 weeks at 80% among patients with triple negative, human epidermal growth factor receptor 2 (HER2)-positive, and hormone refractory metastatic breast cancer patients with leptomeningeal metastasis (LMD) with and without parenchymal brain involvement.


I. To describe the one-year survival in patients with LMD from metastatic breast cancer treated with HD-MTX.

II. To describe the overall progression free survival (PFS) in patients with LMD from metastatic breast cancer treated with HD-MTX.

III. To describe the tolerability of HD-MTX in patients with LMD from metastatic breast cancer.

IV. To describe the cost of HD-MTX treatment in patients with LMD from metastatic breast cancer.

V. To investigate cytologic sterilization following HD-MTX in patients with LMD from metastatic breast cancer.


Patients receive high-dose methotrexate intravenously (IV) over 4 hours on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 14 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Wake Forest University Health Sciences

Principal Investigator
Roy E Strowd

  • Primary ID CCCWFU 74315
  • Secondary IDs NCI-2015-01159, CIR00009368
  • ID NCT02422641