Evaluating high-dose methotrexate for breast cancer with 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 testing if high-dose methotrexate can help breast cancer patients with leptomeningeal disease feel better and improve their treatment options.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 16 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Wake Forest University Health Sciences (other)
• Drugs / interventions: Chemotherapy, methotrexate
• Locations: 3 sites (Baltimore, Maryland and 2 other locations)
• Trial ID: NCT02422641 on ClinicalTrials.gov

What this trial studies

This phase II clinical trial aims to assess the effectiveness of high-dose methotrexate (HD-MTX) in treating patients with metastatic breast cancer who have leptomeningeal disease. The study will involve administering systemic, intravenous HD-MTX, which is known to penetrate the blood-brain barrier and may target areas of poor cerebrospinal fluid flow. The trial is designed to provide prospective data on the use of HD-MTX, addressing a significant unmet clinical need in this patient population. By evaluating the drug's efficacy, the study seeks to inform treatment regimens for leptomeningeal disease in breast cancer patients.

Who should consider this trial

Good fit: Ideal candidates include adults over 18 with confirmed invasive breast cancer, specifically those with triple-negative, HER2-positive, or hormone-refractory subtypes.

Not a fit: Patients with non-invasive breast cancer or those who do not meet the specific subtype criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve outcomes for patients with leptomeningeal metastasis from breast cancer.

How similar studies have performed: While previous retrospective studies have suggested the potential efficacy of HD-MTX for this condition, this is one of the first prospective evaluations, making it a novel approach.

Eligibility criteria

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.

Where this trial is running

Baltimore, Maryland and 2 other locations

• Sidney Kimmel Comprehensive Cancer Center — Baltimore, Maryland, United States (RECRUITING)
• Siteman Cancer Center- Washington University School of Medicine in St. Louis — St Louis, Missouri, United States (ACTIVE_NOT_RECRUITING)
• Comprehensive Cancer Center at Wake Forest University (CCCWFU) — Winston-Salem, North Carolina, United States (RECRUITING)

Study contacts

• Principal investigator: Roy Strowd, MD — Wake Forest University Health Sciences
• Study coordinator: Study Coordinator

Conditions: Metastatic Breast Cancer, Leptomeningeal Disease