Leptomeningeal Disease, Metastatic Breast Cancer
Conditions
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.
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.
Interventions
DRUGHigh-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.
Sponsors
Wake Forest University Health Sciences
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (at 12 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| One year survival | 1 year | 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 | From date of first treatment to the time of systemic or neurologic progression of disease whichever occurs first, assessed up to 2 years | 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 | Up to 2 years | 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 | Up to 2 years | 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. |
| Number of Dose Reductions | Up to 2 years | 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. |
Countries
United States
Contacts
CONTACTSara Cox
CONTACTStrowd Roy, MD
PRINCIPAL_INVESTIGATORRoy Strowd, MD
Wake Forest University Health Sciences
Outcome results
None listed