Clinical Trials /

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

NCT02422641

Description:

Management of leptomeningeal disease (LMD) in patients with metastatic breast cancer is an area of unmet clinical need. High-dose methotrexate (HD-MTX) is known to have activity against breast cancer and in contrast to other systemic chemotherapeutics, it penetrates the blood brain barrier, targets areas of poor cerebrospinal fluid flow, may penetrate bulky leptomeningeal disease, and provide treatment to systemic disease burden. While two retrospective studies have suggested activity of HD-MTX in LMD in patients with breast cancer, no prospective data are available to inform its inclusion in treatment regimens. Thus, while HD-MTX is included in the NCCN Guidelines for LMD and while it is used to varying degrees in cancer centers across the nation, this is more representative of the lack of available therapies for LMD as opposed to strong evidence-based data. This phase II, prospective study will evaluate systemic, intravenous HD-MTX in breast cancer patients with leptomeningeal metastasis with or without brain parenchymal metastasis.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Prospective Evaluation of High-dose (8 g/m2) Systemic <span class="go-doc-concept go-doc-intervention">Methotrexate</span> in Patients With <span class="go-doc-concept go-doc-disease">Breast Cancer</span> and Leptomeningeal Metastasis

Title

  • Brief Title: Prospective Evaluation of High-dose (8 g/m2) Systemic Methotrexate in Patients With Breast Cancer and Leptomeningeal Metastasis
  • Official Title:
  • Clinical Trial IDs

    NCT ID: NCT02422641

    ORG ID: J14166

    Trial Conditions

    Metastatic Breast Cancer

    Leptomeningeal Disease

    Trial Interventions

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

    Trial Purpose

    Management of leptomeningeal disease (LMD) in patients with metastatic breast cancer is an
    area of unmet clinical need. High-dose methotrexate (HD-MTX) is known to have activity
    against breast cancer and in contrast to other systemic chemotherapeutics, it penetrates the
    blood brain barrier, targets areas of poor cerebrospinal fluid flow, may penetrate bulky
    leptomeningeal disease, and provide treatment to systemic disease burden. While two
    retrospective studies have suggested activity of HD-MTX in LMD in patients with breast
    cancer, no prospective data are available to inform its inclusion in treatment regimens.
    Thus, while HD-MTX is included in the NCCN Guidelines for LMD and while it is used to
    varying degrees in cancer centers across the nation, this is more representative of the lack
    of available therapies for LMD as opposed to strong evidece-based data. This phase II,
    prospective study will evaluate systemic, intravenous HD-MTX in breast cancer patients with
    leptomeningeal metastasis with or without brain parenchymal metastasis.

    Detailed Description

    BACKGROUND:

    Management of LMD in patients with metastatic breast cancer is an area of unmet clinical
    need. Increased survival in the era of hormonal and HER2 directed therapies has further
    heightened the need for more effective therapies against the late complications of
    metastatic disease. Prognosis is dismal with median survivals ranging from 6-8 weeks in
    untreated patients and with little improvement having been demonstrated over the past 20
    years.

    Recently, there has been renewed interest in systemic chemotherapeutic options in these
    patients. Incorporation of systemic therapies into standard treatment algorithms has been
    limited as many agents have not been shown to adequately penetrate the blood brain barrier.
    High-dose methotrexate (HD-MTX), however, is unique in that it does penetrate the blood
    brain barrier. In fact, evidence suggests that it may target areas of poor cerebrospinal
    fluid (CSF) flow, penetrate bulk disease, and provide treatment to systemic disease burden.
    Methotrexate is a drug known to have activity against breast cancer and has been used in
    combination with cyclophosphamide and 5-flourouricil as part of a standard adjuvant
    treatment regimen.

    Currently, HD-MTX is included in the NCCN Guidelines for LMD and is used intermittently at
    Johns Hopkins and cancer centers across the nation for LMD in breast cancer. These
    recommendations, however, are more representative of the lack of available therapies for LMD
    as opposed to strong evidence-based data. Only two retrospective studies have suggested that
    HD-MTX may be an effective option for treating central nervous system (CNS) metastasis, both
    with substantial methodological limitations.

    STUDY OBJECTIVE This phase II, prospective study will evaluate systemic, intravenous
    high-dose methotrexate (HD-MTX) in breast cancer patients with leptomeningeal metastasis
    (LMD). The primary objective is to determine if treatment with systemic intravenous HD-MTX
    will result in an overall survival (OS) exceeding 12 weeks among patients with triple
    negative, HER2-positive, and hormone refractory metastatic breast cancer patients with LMD
    with and without parenchymal brain involvement.

    Trial Arms

    Name Type Description Interventions
    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. High-dose Methotrexate (8 gm/m2; HD-MTX)

    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

    - Alanine aminotransferase or aspartate aminotransferase <2.5x the ULN

    - 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 (see Appendix II)

    - Active diabetes insipidus

    - Active mucositis

    - Chemotherapy or stereotactic radiotherapy within the last 2 weeks

    - Whole brain radiotherapy 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

    - 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 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, or with asymptomatic pleural
    effusions with an estimated size >200 mL, or with symptomatic pleural effusion of any
    size will be excluded.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Survival (at 12 weeks)

    Secondary Outcome Measures

    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

    Tolerability as defined by treatment related toxicity, number of treatment delays, or number of dose reductions.

    Cost as defined by the average cost per treatment course per patient.

    Cytologic sterilization as defined as the percent of patients with positive baseline cytology who develop persistently negative cytology during the course of study treatment.

    Trial Keywords