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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

Phase 1/Phase 2
18 Years
75 Years
Not Enrolling
Brain and Central Nervous System Tumors, Breast Cancer, Cognitive/Functional Effects, Drug/Agent Toxicity by Tissue/Organ, Psychosocial Effects of Cancer and Its Treatment

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Trial Information

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



- 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)


- 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

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.

Inclusion Criteria


- 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

- 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


- 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

- 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


- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease

Outcome Time Frame:

1 year after initiation of treatment

Safety Issue:


Principal Investigator

Edward A. Neuwelt, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

OHSU Knight Cancer Institute


United States: Institutional Review Board

Study ID:




Start Date:

November 2013

Completion Date:

December 2016

Related Keywords:

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



Oregon Health & Science University Cancer Institute Portland, Oregon  97239-3098