Liposomal Cytarabine and High-Dose Methotrexate in Treating Patients With Central Nervous System Metastases From Breast Cancer

NCT ID: NCT00992602

Last Updated: 2017-07-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-04-30
• Study Completion Date: 2014-10-31

Brief Summary

This phase II trial studies how well giving liposomal cytarabine and high-dose methotrexate works in treating patients with breast cancer that has spread to the central nervous system. Drugs used in chemotherapy, such as liposomal cytarabine and methotrexate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving liposomal cytarabine with high-dose methotrexate may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To show that treatment with high-dose methotrexate (HD-MTX) in combination with intrathecal (IT) sustained-release cytarabine (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 central nervous system (CNS) metastatic breast cancer treated with the combination of intravenous (IV) HD-MTX and IT Depocyt (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 Depocyt. Radiographic response will be measured by the Macdonald Criteria using imaging (magnetic resonance imaging [MRI]), and cytologic response will be measured by cerebrospinal fluid (CSF) cytology.

IV. To determine the number of treatment cycles needed to achieve radiographic and cytologic response.

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]/neu and/or breast cancer, early onset [BRCA] if applicable).

OUTLINE:

INDUCTION THERAPY (WEEKS 1-6): Patients liposomal cytarabine IT or via lumbar puncture (LP) every 14 days beginning in week 1. Patients also receive high-dose methotrexate IV every 14 days beginning in week 2. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION THERAPY (WEEKS 7-11): Patients achieving complete response (CR), partial response (PR), or stable disease (SD) and CSF negative for malignant cells receive liposomal cytarabine IT or via LP beginning in week 7 and high-dose methotrexate IV beginning in week 8. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY (WEEKS 13-37): Patients achieving CR, PR, or SD and CSF negative for malignant cells receive liposomal cytarabine IT or via LP every 4 weeks beginning in week 13 and high-dose methotrexate IV monthly beginning in week 15. Treatment with liposomal cytarabine repeats every 4 weeks for up to 5 courses and treatment with high-dose methotrexate repeats monthly for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (liposomal cytarabine, high-dose methotrexate)

See Detailed Description

Group Type: EXPERIMENTAL

methotrexate

Intervention Type: DRUG

Given IV

liposomal cytarabine

Intervention Type: DRUG

Given IT or via LP

quality-of-life assessment

Intervention Type: OTHER

Ancillary studies

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

methotrexate

Given IV

Intervention Type: DRUG

liposomal cytarabine

Given IT or via LP

Intervention Type: DRUG

quality-of-life assessment

Ancillary studies

Intervention Type: OTHER

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

amethopterin; Folex; methylaminopterin; Mexate; MTX; cytarabine liposome; DepoCyt; DepoCyte; DepoFoam-encapsulated cytarabine; DTC 101; quality of life assessment

Eligibility Criteria

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
• Able 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 untreated index lesions for follow up must be identified; no treatment with SRS will be permitted while on the study; CNS disease must be documented by MRI and 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%
• Glomerular filtration rate (GFR) >= 60 mL/min
• Previous allergic or adverse reaction to methotrexate or cytarabine
• Prior treatment with systemic HD-MTX, IT liposomal cytarabine, or IT therapy of any kind
• 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 was 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
• Stereotactic radiosurgery (SRS) less than 2 weeks before the start of study therapy
• Any unresolved toxicity greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 from previous anti-cancer therapy
• Previous enrollment in the present study
• Major surgery within 4 weeks prior to starting therapy, with the exception of the Ommaya reservoir which can be used for introduction of chemotherapy within 48-72 hours after placement

Exclusion Criteria

• Any ongoing therapy for systemic disease allows for the 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 must be reviewed and approved by the primary investigator on a case-by-case basis
• Mini-mental state examination score of 24 or above

• 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 > 5 x 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Maciej Mrugala

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Maciej Mrugala

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Locations

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

Other Identifiers

NCI-2009-01309

Identifier Type: REGISTRY

Identifier Source: secondary_id

6954

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

6954

Identifier Type: -

Identifier Source: org_study_id