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

This study is currently recruiting participants.
See Contacts and Locations
Verified December 2016 by Roy Strowd, MD, Comprehensive Cancer Center of Wake Forest University
Sponsor:
Collaborator:
Sidney Kimmel Comprehensive Cancer Center
Information provided by (Responsible Party):
Roy Strowd, MD, Comprehensive Cancer Center of Wake Forest University
ClinicalTrials.gov Identifier:
NCT02422641
First received: April 10, 2015
Last updated: December 13, 2016
Last verified: December 2016
  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 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.

Condition Intervention Phase
Metastatic Breast Cancer Leptomeningeal Disease Drug: High-dose Methotrexate (8 gm/m2; HD-MTX) Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Traditional Incision and Drainage of Cutaneous Abscess Vs. Minimally Invasive Incision and Drainage With Vessel Loop: A Randomized Controlled Trail

Resource links provided by NLM:


Further study details as provided by Roy Strowd, MD, Comprehensive Cancer Center of Wake Forest University:

Primary Outcome Measures:
  • Survival (at 12 weeks) [ Time Frame: 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 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. [ Time Frame: 1 year ]
  • Progression Free Survival [ Time Frame: Patients will be followed until progression, expected average time to progression approximately 8-12 weeks ]
    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 as defined by treatment related toxicity, number of treatment delays, or number of dose reductions. [ Time Frame: Patients will be followed for the duration of study treatment until progression, expected average time to progression approximately 8-12 weeks ]
  • Cost as defined by the average cost per treatment course per patient. [ Time Frame: Patients will be followed for the duration of study treatment until progression, expected average time to progression approximately 8-12 weeks ]
  • Cytologic sterilization as defined as the percent of patients with positive baseline cytology who develop persistently negative cytology during the course of study treatment. [ Time Frame: Patients will be followed for the duration of study treatment until progression, expected average time to progression approximately 8-12 weeks ]

Estimated Enrollment: 16
Study Start Date: April 2015
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High-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.
Drug: High-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.

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-fluorouracil 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (American Society of Clinical Oncology-College of American Pathologists).
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02422641

Contacts
Contact: Cindy Miller cytmill@wakehealth.edu
Contact: Strowd Roy, MD rstrowd@wakehealth.edu

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Joy Fisher       jfisher@jhmi.edu   
United States, North Carolina
Comprehensive Cancer Center at Wake Forest University (CCCWFU) Recruiting
Winston Salem, North Carolina, United States, 27157
Contact: Cindy Miller       cytmill@wakehealth.edu   
Sponsors and Collaborators
Wake Forest University Health Sciences
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Roy Strowd, MD Wake Forest University Health Sciences
  More Information

Responsible Party: Roy Strowd, MD, Clinical Researcher, Comprehensive Cancer Center of Wake Forest University
ClinicalTrials.gov Identifier: NCT02422641     History of Changes
Other Study ID Numbers: CCCWFU 74315
Study First Received: April 10, 2015
Last Updated: December 13, 2016
Individual Participant Data  
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on June 22, 2017