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

Stage IV Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00992602
• Other study ID #: 6954
• Secondary ID: NCI-2009-0130969
• Status: Completed
• Phase: Phase 2
• First received: October 7, 2009
• Last updated: November 7, 2014
• Start date: April 2011
• Est. completion date: October 2014

Study information

• Verified date: November 2014
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: October 2014
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

• Acceptable liver function (see 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

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 > 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

• Prior treatment with whole brain radiotherapy (prior treatment with 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, 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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• methotrexate
Given IV
• liposomal cytarabine
Given IT or via LP

Other:
• quality-of-life assessment
Ancillary studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	University of California Medical Center At Irvine-Irvine Campus	Irvine	California
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
University of Washington	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival free of neurological progression, measured in weeks	Described using Kaplan-Meier survival curves, and confidence intervals for median PFS will be computed.	Time from start of therapy, assessed up to 4 years	No
Primary	Number and percent of patients reporting grade 3+ neurological and systemic adverse events that persists following dose reductions or schedule modifications, assessed using Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria		Up to 30 days post-treatment	Yes
Secondary	Overall survival	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.	Time from start of therapy until death, assessed up to 4 years	No
Secondary	Radiographic response, measured by RECIST using imaging	Best overall response rate and a 90% Wilson score binomial confidence interval will be determined for evaluable subjects.	Up to 4 years	No
Secondary	Cytologic response as measured by CSF cytology (positive or negative for malignant cells)		Up to week 37	No
Secondary	Functional Assessment of Cancer Therapy (FACT)-Brain (Br)/CNS total score and subscales (physical well-being, social/family well-being, emotional well-being, functional well-being, symptom index) using standard scoring	FACT-BR/CNS total score and subscales will be examined longitudinally for the full study cohort, and for groups defined by length of follow-up (pattern-mixture model), using linear mixed effects regression.	Up to 4 years	No