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

Official Title: “A 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”

This phase II trial is studying how well giving high-dose methotrexate together with liposomal cytarabine works in treating patients with 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 central nervous system (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]).

OUTLINE:

INDUCTION THERAPY (weeks 1-6): Patients receive high-dose methotrexate IV over 4 hours on days 1, 15, and 29 and liposomal cytarabine 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.

Intervention(s) in this Clinical Trial

• Drug: methotrexate
  • Given IV
• Drug: liposomal cytarabine
  • Given IT
• Other: quality-of-life assessment
  • Ancillary studies
• Other: questionnaire administration
  • Ancillary studies

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Treatment (chemotherapy)
  • INDUCTION THERAPY (weeks 1-6): Patients receive high-dose methotrexate IV over 4 hours on days 1, 15, and 29 and liposomal cytarabine IT over 5 minutes on days 8, 22, and 36. CONSOLIDATION THERAPY (weeks 7-11): Patients achieving CR, PR, or 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.

Primary Measures

• Progression-free survival (PFS)
  • Time Frame: Weekly
    Safety Issue?: No
• Cancer Therapy Evaluation Program (CTEP) Common Toxicity Criteria grade 3+ neurological and systemic toxicity that persists following dose reductions or schedule modifications
  • Time Frame: Weeks 1-9, week 13, and at withdrawal of study treatment
    Safety Issue?: Yes

Secondary Measures

• Overall survival
  • Time Frame: Periodically after withdrawal of study treatment
    Safety Issue?: No
• Duration of response
  • Time Frame: Periodically after withdrawal of study treatment
    Safety Issue?: No
• Cytologic response as measured by CSF cytology (positive or negative for malignant cells)
  • Time Frame: At screening and then following induction (week 6 or 7), following consolidation (week 11), and every 3 weeks in the maintenance phase
    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: Every 4 weeks during the study
    Safety Issue?: No

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 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%
• 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 < 4.0 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 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

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Fred Hutchinson Cancer Research Center Other

Overall Clinical Trial Officials and Contacts

Maciej Mrugala Principal Investigator Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00992602

Study ID Number: 6954

ClinicalTrials.gov Identifier: NCT00992602

Health Authority: United States: Institutional Review Board