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Phase II Study of the Combination of High-dose Methotrexate and Intrathecal Liposomal Cytarabine in Patients With Leptomeningeal Metastases With or Without Parenchymal Brain Involvement

Phase 2
18 Years
Open (Enrolling)
Central Nervous System Metastases, Leptomeningeal Metastases, Recurrent Breast Cancer, Stage IV Breast Cancer, Tumors Metastatic to Brain

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Trial Information

Phase II Study of the Combination of High-dose Methotrexate and Intrathecal Liposomal Cytarabine in Patients With Leptomeningeal Metastases With or Without Parenchymal Brain Involvement


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.


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

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]).


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


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

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.

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS)

Outcome Description:

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.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Maciej Mrugala

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Institutional Review Board

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Central Nervous System Metastases
  • Leptomeningeal Metastases
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Tumors Metastatic to Brain
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Meningeal Carcinomatosis



Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington  98109
Jonsson Comprehensive Cancer Center Los Angeles, California  90095