High-dose Methotrexate and Liposomal Cytarabine in Treating Patients With CNS Metastases From Breast Cancer

• Progression-free survival (PFS) [ Time Frame: Weekly ] [ Designated as safety issue: No ]
  Described using Kaplan-Meier survival curves, and confidence intervals for median PFS will be computed. A 95% confidence interval lower bound greater than 7 weeks would be strong evidence for efficacy of the combined treatment regimen. However, an observed median PFS of 12 weeks or greater would also show promise for the combined therapy.
• Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria grade 3+ neurological and systemic toxicity that persists following dose reductions or schedule modifications [ Time Frame: Over 9 weeks ] [ Designated as safety issue: Yes ]
• CTEP Common Toxicity Criteria grade 3+ neurological and systemic toxicity that persists following dose reductions or schedule modifications [ Time Frame: Week 13 ] [ Designated as safety issue: Yes ]
• CTEP Common Toxicity Criteria grade 3+ neurological and systemic toxicity that persists following dose reductions or schedule modifications [ Time Frame: At withdrawal of study treatment ] [ Designated as safety issue: Yes ]

• Progression-free survival [ Designated as safety issue: No ]
• Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria grade 3+ neurological and systemic toxicity [ Designated as safety issue: Yes ]

• Overall survival [ Time Frame: Up to 3.5 years ] [ Designated as safety issue: No ]
  Described using Kaplan-Meier survival curves. Measured as time from start of therapy until death, censored on the last date the patient was known to be alive.
• Duration of response [ Time Frame: Up to 3.5 years ] [ Designated as safety issue: No ]
  Described using Kaplan-Meier survival curves. Radiographic response will be measured by the RECIST criteria.
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells) [ Time Frame: At baseline ] [ Designated as safety issue: No ]
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells) [ Time Frame: Week 7 ] [ Designated as safety issue: No ]
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells) [ Time Frame: Week 11 ] [ Designated as safety issue: No ]
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells) [ Time Frame: Up to week 37 ] [ Designated as safety issue: No ]
• FACT-Brain (Br) total score and subscales (physical well-being, social/family well-being, emotional well-being, functional well-being, symptom index) using standard scoring [ Time Frame: Assessed every 4 weeks until withdrawal from study ] [ Designated as safety issue: No ]

• Overall survival [ Designated as safety issue: No ]
• Duration of response [ Designated as safety issue: No ]
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells) [ Designated as safety issue: No ]
• FACIT-Br total score and subscales (physical well-being, social/family well-being, emotional well-being, functional well-being, symptom index) using standard scoring [ Designated as safety issue: No ]

This phase II trial is studying how well giving high-dose methotrexate together with liposomal cytarabine works in treating patients with central nervous system (CNS) metastases from metastatic breast cancer. Drugs used in chemotherapy, such as methotrexate and liposomal cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving high-dose systemic methotrexate with intra-cerebral spinal fluid (CSF) liposomal cytarabine may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To show that treatment with high-dose methotrexate (HD-MTX) in combination with intrathecal (IT) liposomal cytarabine will result in median progression-free survival (PFS) greater than 7 weeks for patients with breast cancer and leptomeningeal metastases with or without parenchymal brain involvement.

SECONDARY OBJECTIVES:

I. To describe the overall survival of patients with CNS metastatic breast cancer treated with the combination of intravenous (IV) HD-MTX and IT liposomal cytarabine.

II. To describe the safety of the combination therapy, in terms of toxicity, adverse events, and the need for dose reductions or schedule modification.

III. To estimate the best overall response rate achieved during treatment with IV HD-MTX and IT liposomal cytarabine. Radiographic response will be measured by the Macdonald Criteria using imaging (magnetic resonance imaging [MRI]), and cytologic response will be measured by CSF cytology.

IV. To determine the number of treatment cycles needed to achieve radiographic and cytologic response. Time to progression and duration of the response will also be measured.

V. To describe response duration in patients who achieve at least partial radiographic response and cytologic clearance.

VI. To define time to clinical progression as measured by Karnofsky performance status (KPS) and neurological exam.

VII. To describe functional status and quality of life of patients, through clinical evaluations of neurological status and patient-reported quality of life (QOL) measured by the Functional Assessment of Chronic Illness Therapy (FACIT) brain and/or CNS questionnaires.

VIII. To correlate response rates with the extent of patient's systemic disease and tumor receptor status (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [Her2]).

TERTIARY OBJECTIVES:

I. To correlate response rates with the extent of patient's systemic disease and tumor receptor status (ER, PR, Her2/neu).

OUTLINE:

INDUCTION THERAPY (weeks 1-6): Patients receive high-dose methotrexate intravenously (IV) over 4 hours on days 1, 15, and 29 and liposomal cytarabine intrathecally (IT) over 5 minutes on days 8, 22, and 36.

CONSOLIDATION THERAPY (weeks 7-11): Patients achieving complete response (CR), partial response (PR), or stable disease (SD) then receive high-dose methotrexate IV over 4 hours on days 43 and 57. Patients also receive liposomal cytarabine IT over 5 minutes on days 50 and 64.

MAINTENANCE THERAPY (weeks 13-37): Patients achieving CR, PR, or SD receive high-dose methotrexate IV over 4 hours once monthly and beginning in week 15, patients receive liposomal cytarabine IT over 5 minutes once monthly. Treatment repeats once monthly for 5-6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Central Nervous System Metastases
• Leptomeningeal Metastases
• Recurrent Breast Cancer
• Stage IV Breast Cancer
• Tumors Metastatic to Brain

• Drug: methotrexate
  Given IV
  Other Names:

  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
• Drug: liposomal cytarabine
  Given IT
  Other Names:

  • cytarabine liposome
  • DepoCyt
  • DepoCyte
  • DepoFoam-encapsulated cytarabine
  • DTC 101
• Other: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment
• Other: questionnaire administration
  Ancillary studies

Inclusion Criteria:

• Women who are not pregnant (contraception must be used throughout the study)
• Diagnosis of breast cancer with metastases to CNS (regardless of receptor status), leptomeningeal disease must be present with/without parenchymal brain involvement
• Ability to provide informed consent
• No prior treatment with whole brain radiotherapy (WBRT)
• If patient received stereotactic radiosurgery (SRS) prior to enrollment it must be well documented which lesions were treated and index lesions (untreated) for follow up must be identified, no treatment with SRS will be permitted while on the study
• CNS disease must be documented by magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology
• Karnofsky Performance Status > 60
• White blood cells (WBC) > 3.0 K
• Absolute neutrophil count (ANC) > 1.5 K
• Platelets (PLT) > 100 K
• Hematocrit (HCT) > 30%
• Acceptable renal function (glomerular filtration rate [GFR] >= 60 mL/min)
• Acceptable liver function (see exclusion criteria)
• Well controlled systemic disease
• Therapy for systemic disease allowing for addition of systemic HD-MTX and IT Depocyt (in general patients receiving trastuzumab or lapatinib at the time of enrollment will be allowed to continue); bisphosphonates (i.e., zoledronic acid) and denosumab will be allowed; other non-CNS active chemotherapies might be allowed if no known interactions with study drugs are present; this will be reviewed on case-by-case basis
• Mini-mental status examination score of 24 or above

Exclusion Criteria:

• Serum bilirubin > 1.5 x the upper limit of reference range (ULRR)
• Serum creatinine > 1.5 x ULRR or creatinine clearance =< 60 mL/minute (calculated by Cockcroft-Gault formula)
• Potassium, < 3.7 mmol/L despite supplementation; serum calcium (ionized or adjusted for albumin,) or magnesium out of normal range despite supplementation
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULRR
• Alkaline phosphatase (ALP) > 2.5 x ULRR or > 5x ULRR if judged by the investigator to be related to liver metastases
• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
• Patients with known pleural effusion or ascites
• Prior treatment with whole brain radiotherapy, prior treatment with stereotactic radiosurgery (SRS) is allowed under conditions provided in the inclusion criteria
• Previous allergic or adverse reaction to methotrexate or cytarabine
• Prior treatment with systemic HD-MTX or IT liposomal cytarabine
• Prior IT therapy of any kind
• Women who are currently pregnant or breast feeding
• Previous or current malignancies of other histologies within the last 5 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
• Receipt of any investigational agents within 30 days prior to commencing study treatment
• Last dose of prior chemotherapy discontinued less than 4 weeks before the start of study therapy; patients who had no toxicities with prior chemotherapy can start study treatment earlier than 4 weeks
• Last radiation therapy to the brain in the form of SRS within the last 2 weeks before the start of study therapy
• Any unresolved toxicity greater than Common Toxicity Criteria (CTC) grade 1 from previous anti-cancer therapy
• Previous enrollment in the present study
• Major surgery within 4 weeks prior to starting therapy, Ommaya reservoir can be used for introduction of chemotherapy within 48-72 hours after placement