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.
Adults (male and female) age >18
Eastern Cooperative Group (ECOG) Performance Scale 0-1 (see Appendix I)
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.
Prior allergy or adverse reaction to methotrexate
New York Heart Association Heart Failure Class >3
Active diabetes insipidus
Active mucositis
Single group
High-dose Methotrexate (8 gm/m2; HD-MTX)
DrugEnrolled 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.
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.
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.
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.
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).
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.
Treatment Cost
As defined by the average cost per treatment course per patient.
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.
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Wake Forest University Health Sciences
Lead sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborator
National Cancer Institute (NCI)
Collaborator
