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

This study has been withdrawn prior to enrollment.
(after original approval, IRB closed enrollment; major revisions required to re-open.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT00397501
First received: November 8, 2006
Last updated: October 25, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Breast Cancer
Cognitive/Functional Effects
Drug/Agent Toxicity by Tissue/Organ
Psychosocial Effects of Cancer and Its Treatment
Biological: trastuzumab
Drug: carboplatin
Drug: methotrexate
Drug: sodium thiosulfate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Pilot Study of Patients With Brain Metastasis Secondary to Breast Cancer Treated With Methotrexate and Carboplatin in Conjunction With Blood-Brain Barrier Disruption, With Concurrent Trastuzumab in HER-2 Positive Patients

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease [ Time Frame: 1 year after initiation of treatment ] [ Designated as safety issue: No ]
  • Overall survival exceeding 5 months in patients with HER2-positive disease [ Time Frame: 1 year after initiation of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: 5 years after intitiation of treatment ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Complete response rate [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Time to best response [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Quality of life [ Time Frame: 5 years ] [ Designated as safety issue: No ]

Enrollment: 0
Study Start Date: October 2013
Estimated Study Completion Date: October 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: HER-2 positive subjects
HER-2 positive subjects treated with trastuzumab
Biological: trastuzumab

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

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

Other Name: Herceptin
Drug: 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
Other Name: carbo
Drug: methotrexate
2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion
Other Name: MTX
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
Other Name: STS
Active Comparator: HER-2 negative subjects
HER-2 negative subjects not treated with trastuzumab
Drug: 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
Other Name: carbo
Drug: methotrexate
2500 mg/day x 2 days; total dose 5000mg Infused over 10mins in 200ml saline beginning immediately after mannitol infusion
Other Name: MTX
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
Other Name: STS

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed breast cancer metastatic to the central nervous system (as documented by brain biopsy, cytology [analysis from cerebrospinal fluid]) OR radiographic evidence of brain metastasis with a diagnosis of systemic breast cancer
  • Patients must have stable or no systemic disease as determined by a CT scan of the chest, abdomen, and pelvis
  • HER2-positive or -negative disease by fluorescent in situ hybridization (FISH) or immunohistochemistry
  • Patients with HER2-positive disease and signs of intracranial herniation and/or spinal block may first undergo intraarterial chemotherapy off study (with carboplatin, methotrexate, and trastuzumab [Herceptin®] by the same routes used on study) until radiographically shown to be safe to undergo blood brain barrier disruption, at which point they may be enrolled in the study
  • Hormone receptor status not specified

PATIENT CHARACTERISTICS:

  • Female
  • Menopausal status not specified
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Life expectancy > 6 weeks
  • Hematocrit ≥ 25%
  • WBC ≥ 2,500/mm³
  • Absolute neutrophil count ≥ 1,200/mm³
  • Platelet count ≥100,000/mm³
  • Creatinine clearance ≥ 50 mL/min (eligible for full-dose methotrexate) (30-49 mL/min allowed for patients receiving reduced-dose methotrexate)
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00397501

Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Principal Investigator: Edward A. Neuwelt, MD OHSU Knight Cancer Institute
  More Information

No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT00397501     History of Changes
Other Study ID Numbers: OHSU-2188, 2188, SOL-06015
Study First Received: November 8, 2006
Last Updated: October 25, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by OHSU Knight Cancer Institute:
cognitive/functional effects
psychosocial effects of cancer and its treatment
drug/agent toxicity by tissue/organ
recurrent breast cancer
stage IV breast cancer
adult tumors metastatic to brain

Additional relevant MeSH terms:
Breast Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Nervous System Diseases
Trastuzumab
Carboplatin
Methotrexate
Sodium thiosulfate
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antidotes

ClinicalTrials.gov processed this record on October 01, 2014