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
18 Years
75 Years
Female
Brain and Central Nervous System Tumors, Breast Cancer, Cognitive/Functional Effects, Drug/Agent Toxicity by Tissue/Organ, Psychosocial Effects of Cancer and Its Treatment
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
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.
Inclusion 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
Type of Study:
Interventional
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:
No
Principal Investigator
Edward A. Neuwelt, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
OHSU Knight Cancer Institute
Authority:
United States: Institutional Review Board
Study ID:
OHSU-2188
NCT ID:
NCT00397501
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
Name | Location |
|---|---|
| Oregon Health & Science University Cancer Institute | Portland, Oregon 97239-3098 |
