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.
- 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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall survival exceeding 5 months in patients with Human Epidermal growth factor Receptor 2(HER2)-negative disease
1 year after initiation of treatment
Edward A. Neuwelt, MD
OHSU Knight Cancer Institute
United States: Institutional Review Board
|Oregon Health & Science University Cancer Institute||Portland, Oregon 97239-3098|