Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis
The main purpose of this study is to investigate the efficacy of bevacizumab, etoposide and cisplatin in treating breast cancer patients with central nervous system metastasis (including brain parenchymal and leptomeningeal metastasis).
Drug: Bevacizumab, etoposide, cisplatin
Drug: Intrathecal methotrexate
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis|
- Response rate of central nervous system (CNS) metastasis [ Time Frame: 1 year ] [ Designated as safety issue: No ]
The response criteria for brain parenchymal metastasis is measured according to the volumetric response criteria with modification. CNS lesion(s) which have a ≧ 50% volumetric reduction of in the absence of progressive neurologic signs and symptoms will be considered as responsive.
The response criteria for leptomeningeal metastasis is defined as disappearance of carcinoma cells of three consecutive cytology examination of cerebrospinal fluid (CSF) after chemotherapy. For patients with both brain and leptomeningeal metastases, both criteria need to be met to be considered as responsive.
- Number of participants with adverse events [ Time Frame: Baseline to until one month after last course of chemotherapy protocol treatment ] [ Designated as safety issue: Yes ]To observe the toxicity profile of B-EP according to CTCAE 3.0
- To evaluate the response rate of breast cancer patients with brain parenchymal metastasis after receiving B-EP [ Time Frame: 1 year ] [ Designated as safety issue: No ]To use volumetric measurement by subtraction image of CT the tumor before and after contrast enhancement; assessed every 9 weeks until best response measured
- To evaluate the response rate of breast cancer patients with leptomeningeal carcinomatosis after receiving B-EP [ Time Frame: 1 year ] [ Designated as safety issue: No ]A response is defined as the CSF cytology examination turns from positive to negative. A confirmed response is defined as CSF cytology examination remains negative for two or three consecutive tests
- To evaluate the response rate of extra-CNS lesions according to RECIST [ Time Frame: 1 year ] [ Designated as safety issue: No ]To evaluate the response rate of extra-CNS lesions according to RECIST. Measure every 9 weeks until best response recorded
- Vascular activity of brain metastatic tumors after bevacizumab treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]vascular activity detected with dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), measured before treatment, 24 hours after bevacizumab administration and end of 1st cycle of B-EP
- Biomarkers in CSF and serum in patients with brain and/or leptomeningeal metastasis receiving B-EP [ Time Frame: Before the start of treatment till the end of treatment (after 6 cycles or progression) ] [ Designated as safety issue: No ]Prognostic and predictive value of biomarkers in CSF or serum. Serum will be drawn before treatment, end of cycle one and end of 6 cycles of treatment or time of progression
- Drug concentrations of etoposide and cisplatin [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]Drug concentrations of bevacizumab, etoposide in CSF, blood and CSF/blood ratio before and after B-EP treatment in cycle one and cycle two
- Association between response of CNS metastasis and the history of prior exposure to cisplatin [ Time Frame: 1 year ] [ Designated as safety issue: No ]To evaluate the response rate and duration of response of CNS metastasis regarding to prior exposure to cisplatin
- Proton MR spectroscopy of metastatic brain tumor before and after B-EP treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]To evaluate the characteristics of 1H-MRS of metastatic brain tumor before and after B-EP treatment
|Study Start Date:||January 2011|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||July 2013 (Final data collection date for primary outcome measure)|
|Experimental: Bevacizumab, etoposide, cisplatin (BEEP)||
Drug: Bevacizumab, etoposide, cisplatin
Bevacizumab (15mg/kg) on D1, etoposide (70mg/m2) on D2-D4, cisplatin (70mg/m2) on D2; 21 days a cycle, for a maximum of 6 cycles
Other Name: Bevacizumab (Avastin)Drug: Intrathecal methotrexate
Additional intrathecal methotrexate only given in patients with leptomeningeal metastasis
Other Name: Methotrexate
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Brain metastases are increasingly important causes of morbidity and mortality in breast cancer patients. Whole brain radiotherapy (WBRT) and surgery remains the standard treatment for brain metastases. However, the median overall survival after brain and leptomeningeal metastasis were only 8.5 months and 16 weeks respectively There is lack of standard treatment for brain metastasis progression post WBRT. Chemotherapy was considered mostly poor for treatment response because of the blood brain barrier. However, this has been questioned because tumor can disrupt the normal function of blood brain barrier. For example, etoposide and cisplatin had been used for treatment for breast cancer patients with brain metastasis. The overall response rate of central nervous system (CNS) was 39 %, disease control rate was 60%, although the median overall survival was 31 weeks only. The role of targeted therapies is actively being assessed. Recently, a phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer showed that CNS objective response rates were 6% to lapatinib monotherapy and 20% to lapatinib plus capecitabine. Although the result is promising, the treatment population is limited in the HER2 overexpression breast cancer.
Bevacizumab, an anti-angiogenic agent, has been approved to combine with several chemotherapy agents in breast, lung and colon cancer. It was once considered contraindicated in patients with brain metastases due to the possibility of intracranial bleeding. However, two studies involving the use of bevacizumab for treating brain metastatic tumors of non-squamous or peripherally located squamous lung cancer showed no report of brain hemorrhage. In addition, bevacizumab has been approved to treat primary brain aggressive tumors recently.
In the institution, the investigators treated three breast cancer patients with multiple brain metastases using bevacizumab plus etoposide and cisplatin (B-EP). All of them have been treated for at least two lines of chemotherapy before brain metastases occurred. All of them received WBRT for brain metastases and one of them also received craniotomy with brain tumor resection plus local stereotactic radiosurgery. The follow up magnetic resonance imaging (MRI) had revealed recurrent metastatic brain tumors in one patients, and recurrence of leptomeningeal metastasis in another two patients. One patient who has multiple brain parenchyma metastases showed objective response on MRI after two cycle of B-EP treatment, and remained progression free for more than 5 months. The other two patients with leptomeningeal metastasis had intrathecal and intraventricular (via Ommaya reservoir) methotrexate treatment for more than eight doses. They were near stupor before B-EP treatment. Both had best clinical response of full recovery of consciousness and absence of cancer cells in cerebrospinal fluid. One survived eight months after the diagnosis leptomeningeal metastasis, and the other two were still alive six months after the diagnosis of leptomeningeal metastasis .
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been used in various studies for evaluation of anti-angiogenic condition. In breast cancer, DCE-MRI has been used as an early predictive marker for response. Glioblastoma patients have also been evaluated with DCE-MRI to determine reduction of vessel permeability after bevacizumab treatment.
Proton magnetic resonance spectroscopy (1H-MRS) has been used to different benign brain tumors from malignant ones. The utilization of 1H-MRS, especially in human brain tumors, coupled to both routine MRI and functional MRI techniques provides greater information concerning tumor grading and extension and characterization of the normal surrounding tissue than what is possible with any other imaging technique alone. To analyze proton spectroscopy before and after bevacizumab may give us further information about the mechanism of B-EP on CNS metastasis.
Therefore, the investigators propose to conduct a phase II clinical trial to test the efficacy of B-EP regimen in breast cancer patients with CNS metastasis along with brain DCE-MRI to demonstrate the antiangiogenesis efficacy.
|Contact: Yen-Shen Lu, MD, PhD||886-2-23123456 ext firstname.lastname@example.org|
|Contact: Ching-Hung Lin, MD||886-2-23123456 ext email@example.com|
|Department of Oncology, National Taiwan University Hospital||Recruiting|
|Taipei City, Taiwan, 100|
|Contact: Yen-Shen Lu, MD, PhD 886-2-23123456 ext 67009 firstname.lastname@example.org|
|Principal Investigator: Yen-Shen Lu, MD, PhD|
|Principal Investigator:||Yen-Shen Lu, MD, PhD||Department of Oncology, National Taiwan University Hospital|