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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression-free survival (PFS)
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.
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
United States: Institutional Review Board
|Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium||Seattle, Washington 98109|
|Jonsson Comprehensive Cancer Center||Los Angeles, California 90095|