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

NCT02422641 | Recruiting Phase 2 FDA Drug

• 2 other identifiers: IRB00035551CCCWFU 74315
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Metastatic Breast Cancer; Leptomeningeal Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• One year survival

  1 year

• Progression Free Survival

  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

  Up to 2 years

• Number of Treatment Delays

  Up to 2 years

• Number of Dose Reductions

  Up to 2 years

Other Outcomes (2)

• Treatment Cost

  Up to 2 years

• Percentage of Cytologic Sterilization

  Up to 2 years

Study Arms (1)

High-dose Methotrexate (8 gm/m2; HD-MTX)

EXPERIMENTAL

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)

Interventions

High-dose Methotrexate (8 gm/m2; HD-MTX) DRUG

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.

High-dose Methotrexate (8 gm/m2; HD-MTX)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead
• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: collaborator

Study Sites (3)

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

RECRUITING

Siteman Cancer Center- Washington University School of Medicine in St. Louis

St Louis, Missouri, 63130, United States

ACTIVE NOT RECRUITING

Comprehensive Cancer Center at Wake Forest University (CCCWFU)

Winston-Salem, North Carolina, 27157, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms; Meningeal Neoplasms

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Roy Strowd, MD

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Study Coordinator

CONTACT

Efrat.Tsivian@Advocatehealth.org

Strowd Roy, MD

CONTACT

rstrowd@wakehealth.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2015
• First Posted: April 21, 2015
• Study Start: May 1, 2015
• Primary Completion: May 1, 2026
• Study Completion (Estimated): July 1, 2027
• Last Updated: March 23, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)