BBBD Followed By Methotrexate and Carboplatin With or Without Trastuzumab in Treating Women With Breast Cancer That Has Spread to the Brain

NCT ID: NCT00397501

Last Updated: 2017-04-21

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2013-10-31

Brief Summary

RATIONALE: Osmotic blood-brain barrier disruption uses certain drugs, such as mannitol, to open the blood vessels around the brain and allow tumor-killing substances to be carried directly to the brain. Drugs used in chemotherapy, such as methotrexate and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Trastuzumab may also help methotrexate and carboplatin work better by making tumor cells more sensitive to the drugs. Giving osmotic blood-brain barrier disruption together with methotrexate, carboplatin, and trastuzumab may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of carboplatin when given together with methotrexate and trastuzumab after mannitol in treating women with breast cancer that has spread to the brain.

Detailed Description

OBJECTIVES:

Primary

• Determine the safety and toxicity associated with blood-brain barrier disruption comprising transfemoral mannitol followed by methotrexate and carboplatin with or without trastuzumab (Herceptin®) in women with brain metastasis secondary to breast cancer. (Phase I)
• Determine if overall survival exceeds 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-positive or HER2-negative disease treated with this regimen. (Phase II)

Secondary

• Determine the overall survival of these patients.
• Compare the event-free and overall survival, steroid use, response rates, and time to best response in patients with HER2-positive vs HER2-negative disease.
• Assess the quality of life of patients treated with this regimen.
• Assess the neuropsychological effects of this treatment regimen in these patients.
• Determine cerebrospinal fluid levels of trastuzumab before and after blood-brain barrier disruption.

OUTLINE: This is a multicenter, phase I, pilot, dose-finding study of carboplatin followed by a phase II, open-label study.

• Phase I: Patients undergo osmotic blood-brain barrier disruption (BBBD) comprising mannitol by transfemoral catheterization followed by methotrexate intra-arterially (IA) over 10 minutes and carboplatin IA over 10 minutes on days 1 and 2. Patients also receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after each dose of carboplatin; leucovorin calcium IV or orally every 6 hours on days 3-9; and pegfilgrastim subcutaneously (SC) on day 4 or filgrastim (G-CSF) SC beginning on day 4 and continuing until blood counts recover (7-10 days). Patients with HER-2 positive disease receive trastuzumab (Herceptin®) IV over 90 minutes within 48 hours prior to BBBD and then weekly for 3 weeks (between BBBD therapy sessions). Treatment repeats every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive decreasing doses of carboplatin and/or methotrexate if the proposed dose is not well tolerated. Dose-limiting toxicity is defined as grade IV hematologic toxicity with delay in subsequent treatment courses for 4 weeks OR grade III/IV nonhematologic toxicity without recovery in 14 days during the course of treatment.

• Phase II: Patients undergo BBBD as in phase I and receive carboplatin and methotrexate at the doses determined in phase I. Patients also receive sodium thiosulfate, leucovorin calcium, and pegfilgrastim or G-CSF as in phase I. Patients with HER2-positive disease also receive trastuzumab as in phase I.

Neuropsychological assessment is performed at baseline, every 6 months during treatment, every 6 months for 1 year, and then annually thereafter. Quality of life is assessed at baseline, every 3 months during treatment, at the completion of study treatment, every 6 months for 1 year, and then annually thereafter.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 78 patients will be accrued for this study.

Conditions

Brain and Central Nervous System Tumors; Breast Cancer; Cognitive/Functional Effects; Drug/Agent Toxicity by Tissue/Organ; Psychosocial Effects of Cancer and Its Treatment

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HER-2 positive subjects

HER-2 positive subjects treated with trastuzumab

Group Type: ACTIVE_COMPARATOR

trastuzumab

Intervention Type: BIOLOGICAL

Trastuzamab, 6mg/kg, within 48 hrs before BBBD

Then, Trastuzumab, 2mg/kg, weekly until next BBBD Then continue for 12 cycles

carboplatin

Intervention Type: DRUG

200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion

methotrexate

Intervention Type: DRUG

2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion

sodium thiosulfate

Intervention Type: DRUG

STS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2

HER-2 negative subjects

HER-2 negative subjects not treated with trastuzumab

Group Type: ACTIVE_COMPARATOR

carboplatin

Intervention Type: DRUG

200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion

methotrexate

Intervention Type: DRUG

2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion

sodium thiosulfate

Intervention Type: DRUG

STS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2

Interventions

trastuzumab

Trastuzamab, 6mg/kg, within 48 hrs before BBBD

Then, Trastuzumab, 2mg/kg, weekly until next BBBD Then continue for 12 cycles

Intervention Type: BIOLOGICAL

carboplatin

200mg/m2/day x 2 days; total dose 400mg/m2 Infused i.a. over 10 mins in 200ml of normal saline after MTX infusion

Intervention Type: DRUG

methotrexate

2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion

Intervention Type: DRUG

sodium thiosulfate

STS dose admin i.v. over 15mins @ 4hrs post carboplatin = 20gm/m2; STS dose admin i.v. over 15mins @ 8hrs post carboplatin = 16gm/m2

Intervention Type: DRUG

Other Intervention Names

Herceptin; carbo; MTX; STS

Eligibility Criteria

Inclusion Criteria

• Bilirubin ≤ 2.0 times upper limit of normal
• LVEF normal by echocardiogram or MUGA
• Adequate pulmonary and cardiac function to tolerate general anesthesia as determined by physical examination and history
• No New York Heart Association class III-IV heart disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known allergy to trastuzumab (HER2-positive patients), carboplatin, methotrexate, or sodium thiosulfate
• No hepatitis B or C positivity
• No uncontrolled intercurrent illness including, but not limited to, any of the following:

• Ongoing or active infection (e.g., HIV)
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situations that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• Prior surgery or biopsy allowed
• Prior chemotherapy and radiation therapy for metastatic breast cancer allowed
• No radiation or cytotoxic chemotherapy within the past 4 weeks (except trastuzumab or hormone therapy that has been part of the patient's ongoing treatment [e.g., aromatase inhibitors for estrogen receptor positive patients])
• No noncytotoxic regimens (e.g., targeted oral agents) within the past 2 weeks
• No investigational agents within the past 4 weeks
• No other concurrent anticancer agents or therapies

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

OHSU Knight Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Edward Neuwelt

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Edward A. Neuwelt, MD

Role: PRINCIPAL_INVESTIGATOR

OHSU Knight Cancer Institute

Other Identifiers

2188

Identifier Type: OTHER

Identifier Source: secondary_id

SOL-06015

Identifier Type: OTHER

Identifier Source: secondary_id

OHSU-2188

Identifier Type: OTHER

Identifier Source: secondary_id

IRB00002188

Identifier Type: -

Identifier Source: org_study_id