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

Traditional Incision and Drainage of Cutaneous Abscess Vs. Minimally Invasive Incision and Drainage With Vessel Loop: A Randomized Controlled Trail

This study is a prospective evaluation of systemic, intravenous high-dose methotrexate (HD-MTX, 8 g/m2) in patients with triple negative, HER2-positive, and hormone refractory breast cancer with leptomeningeal metastasis (LMD) with or without brain parenchymal involvement.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Breast Cancer; Leptomeningeal Disease
• Intervention / Treatment: Drug: High-dose Methotrexate (8 gm/m2; HD-MTX)

Detailed Description

Primary Objective:

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

Secondary and Exploratory Objectives

• To describe the one-year survival in patients with LMD from metastatic breast cancer treated with HD-MTX.
• To describe the overall progression free survival (PFS) in patients with LMD from metastatic breast cancer treated with HD-MTX.
• To describe the tolerability of HD-MTX in patients with LMD from metastatic breast cancer.
• To describe the cost of HD-MTX treatment in patients with LMD from metastatic breast cancer.
• To investigate cytologic sterilization following HD-MTX in patients with LMD from metastatic breast cancer.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Strowd Roy, MD; Email: rstrowd@wakehealth.edu
• Study Contact Backup: Name: Study Coordinator; Email: Efrat.Tsivian@Advocatehealth.org

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Sidney Kimmel Comprehensive Cancer Center
      • Contact: Joy Fisher; Email: jfisher@jhmi.edu
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Active, not recruiting
      • Siteman Cancer Center- Washington University School of Medicine in St. Louis
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Comprehensive Cancer Center at Wake Forest University (CCCWFU)
      • Contact: Roy Strowd, MD; Email: rstrowd@wakehealth.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• 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 or <5x the ULN if secondary to liver metastasis Alanine aminotransferase or aspartate aminotransferase <2.5x the ULN or <5x the ULN if secondary to liver metastasis 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
• 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 (26)
• 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 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 (Appendix IV), or with asymptomatic pleural effusions with an estimated size >200 mL, or with symptomatic pleural effusion of any size will be excluded.

NOTE: Systemic staging of the chest/abdomen/pelvis is required for study entry. See Sections 8.1.9. Body fluid will be assessed based on this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: High-dose Methotrexate (8 gm/m2; HD-MTX); Enrolled patients will undergo treatment with HD-MTX (8 g/m2) as per current standard practice on an every 2 week schedule until disease progression or death from any cause. Treatment will be performed according to standard clinical practice. Surveillance imaging with or without cytologic evaluation will be performed as per standard clinical practice after every 2 cycles (~28 days). Treatment will continue until there is unequivocal evidence of clinical or radiographic CNS or systemic disease progression, death from any cause, or intolerance.

Drug: High-dose Methotrexate (8 gm/m2; HD-MTX); Enrolled patients will undergo treatment with HD-MTX (8 g/m2) as per current standard practice on an every 2 week schedule until disease progression or death from any cause. Treatment will be performed according to standard clinical practice. Surveillance imaging with or without cytologic evaluation will be performed as per standard clinical practice after every 2 cycles (~28 days). Treatment will continue until there is unequivocal evidence of clinical or radiographic CNS or systemic disease progression, death from any cause, or intolerance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (at 12 weeks)	The primary endpoint is survival at 12 weeks from first date of treatment. For the primary analysis, this will be dichotomized according to whether the patient achieves an OS greater than 12 weeks (i.e. survival rate). This cutoff has been selected based on reported OS data in historical controls.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One year survival	As defined as the proportion of patients with time to death greater than 12 months from the time of first date of treatment.	1 year
Progression Free Survival	Progression free survival as defined as the time from first date of treatment to the time of systemic or neurologic progression of disease whichever occurs first. Neurologic progression will be defined as the minimum of clinical or radiographic progression. Clinical neurologic progression will be defined by neurologic examination demonstrating objective, new neurologic deficit attributable to the underlying LMD. Radiographic progression (neurologic or systemic) will be defined by RECIST criteria.	From date of first treatment to the time of systemic or neurologic progression of disease whichever occurs first, assessed up to 2 years
Tolerability of Treatment - Number of Grade 3 or Higher Adverse Events	Toxicity as grade 3 and higher will be tabulated by reporting period, where reporting period is defined to be the planned 14 day period between administrations of high-dose methotrexate (HD MTX).	Up to 2 years
Number of Treatment Delays	Toxicities related to dose delays will be recorded by reporting period, where reporting period is defined to be the planned 14 day period between administrations of HD MTX. The number of times treatment is delayed divided by the number of reporting periods administered to all patients on study will be used to characterize the fraction of times treatments must be delayed.	Up to 2 years
Number of Dose Reductions	Toxicities related to dose delays will be recorded by reporting period, where reporting period is defined to be the planned 14 day period between administrations of HD MTX. The number of times treatment is delayed divided by the number of reporting periods administered to all patients on study will be used to characterize the fraction of times treatments must be delayed.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Cost	As defined by the average cost per treatment course per patient.	Up to 2 years
Percentage of Cytologic Sterilization	As defined as the percent of patients with positive baseline cytology who develop persistently negative cytology during the course of study treatment.	Up to 2 years

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Roy Strowd, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: April 10, 2015
• First Submitted That Met QC Criteria: April 20, 2015
• First Posted (Estimated): April 21, 2015

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Nervous System Neoplasms; Central Nervous System Neoplasms; Skin and Connective Tissue Diseases; Breast Neoplasms; Meningeal Neoplasms; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pterins; Pteridines; Aminopterin; Methotrexate
• Other Study ID Numbers: IRB00035551; P30CA012197 (U.S. NIH Grant/Contract); CCCWFU 74315 (Other Identifier: WFCCC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No