Due to poor accrual this study is being closed to accrual

The purpose of this study is to assess the efficacy and safety of concurrent whole brain radiotherapy (WBRT) and capecitabine followed by combination capecitabine and sunitinib in treating patients with CNS metastases from breast cancer.

Central nervous system (CNS) metastases is the most common type of brain malignancy, and breast cancer is the second most common type of malignancy to cause CNS metastases. Although the incidence of CNS metastases is less common than bone or visceral metastases, it is associated with poorer prognosis and is relatively unresponsive to systemic therapies. The incidence of CNS metastases in breast cancer has been estimated as 1-16% in clinical series, with higher rates (18-30%) in autopsy series. Recently a trend towards increasing CNS relapse has been noted, up to 25-34%. This may be partly explained by the increasing use of contrast-enhanced magnetic resonance imaging (MRI), heightened awareness by patient or clinicians, or an alteration in the natural history of breast cancer with improvements in systemic therapies, resulting in a prolongation of survival. Therefore, with improvements in treatments, metastases are better controlled, resulting in the CNS becoming a sanctuary for residual disease. The treatment of CNS metastases in breast cancer remains challenging. Surgical resection of tumor will prolong survival only in patients with a single lesion and with well controlled systemic disease. For patients with multiple lesions, whole brain radiotherapy (WBRT) remains the backbone in the management of CNS metastases. Recently the use of stereotactic radiosurgery alone or in combination with WBRT has been explored. Although better local control was achieved with the combination therapy, minimal overall survival benefit was seen. This may be secondary to the competing risk of death from systemic (extra-CNS) progression. The use of systemic agents including chemotherapy and hormonal therapy has been generally disappointing. This is often attributed to the impermeability of the blood-brain and blood-tumor barriers. Furthermore, P-glycoprotein (Pgp), a drug efflux pump encoded by the multidrug resistance gene, mdR1, is expressed in brain endothelial cells. Therefore, agents such as doxorubicin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel and vinorelbine, which are active against breast cancer, may either penetrate CNS poorly, or be transported out of the CNS environment. However, the blood brain barrier may be more leaky and permeable than previously thought in patients with CNS metastases, and these agents may achieve therapeutic concentrations in the CNS. As evidence for this, patients without prior exposure to agents such as cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and doxorubicin, can have significant objective responses in the CNS metastases. Today, most patients would have received these agents in the adjuvant setting, thus emphasizing the importance of both chemo-sensitivity together with CNS penetration, in the treatment of CNS metastases.

This is a single arm, open label, phase II drug study. This study will be conducted at the Breast Care Center at Baylor College of Medicine and its affiliated hospital, and at Ben Taub General Hospital in Houston. Patients who were diagnosed with CNS metastases (brain +/- leptomeningeal disease) will be identified prospectively. All eligible patients will receive capecitabine concurrently with WBRT followed by combination capecitabine with sunitinib. WBRT will be administered at 30 Gy in 10 fractions together with capecitabine to be given on the first day of WBRT at 1000 mg/m2/day and continued daily for 14 days. After a 7 days rest period, capecitabine will be restarted at 2000mg/m2/day for 14 days followed by a 7 days rest period. This will be given together with sunitinib at 37.5 mg daily. This is the dosing determined by the phase I study with capecitabine and sunitinib. Dose reduction and/or treatment postponement will be done for significant toxicity. Capecitabine with sunitinib will be administered until disease progression in either CNS and/or non-CNS sites. Efficacy assessments will be performed on all subjects via imaging studies in the CNS and extra-CNS sites 8 weeks after starting study, then every 12 weekly. Neurological examination will be performed at baseline, 3 weeks after starting treatment, then every 6 weekly. Assessment of treatment toxicity will be performed at baseline, 3 weeks after starting treatment, then every 3 weekly using the NCI Common Toxicity grading system. Clinical and laboratory parameters will be assessed until disease progression or withdrawal from study (due to unacceptable toxicity or withdrawal of consent). Subjects with progression of CNS and / or extra-CNS disease will be considered progressors. Subjects withdrawn from treatment will be followed for survival until death.

Primary endpoint: 1. To determine progression free survival. Progression will be defined by progression in either CNS or extra-CNS metastases. Secondary endpoint: 1. To assess the toxicities associated with the regimen 2. To determine the overall objective response in CNS disease 3. To determine the overall objective response in extra-CNS disease 4. To determine the overall survival.

Inclusion Criteria:

Patients must be age 18 or older. Histological or cytologically confirmed invasive breast cancer, with Stage IV disease.

Evidence of radiographically measurable CNS metastases (greater than or equal to 10mm on T1-weighted gadolinium-enhanced MRI) within 2 weeks prior to starting treatment. Patients without known extra-CNS disease are eligible.

Must have metastases in the brain. Patients with concurrent leptomeningeal carcinomatosis are eligible for the study. Local radiation to sites of meningeal involvement in the spine is allowed.

No prior whole brain radiation. Patients who had previous stereotactic brain irradiation are eligible, provided they have new measurable brain lesions (which has not been radiated previously) and will receive WBRT at 30Gy over 10 fractions.

May undergo surgical resection of CNS metastases if clinically indicated, but must have remaining measurable disease in the brain after surgery.

No prior treatment with capecitabine in the adjuvant or metastatic settings. Patients may have completed 5-fluorouracil based treatment in the adjuvant setting or metastatic setting more than one year prior.

Patients who had previous trastuzumab therapy will be eligible but treatment will be discontinued prior to enrollment.

Cardiac ejection fraction within institutional range of normal as measure by echocardiogram or MUGA scans at baseline.

Hematological adequacy Hepatic adequacy Renal adequacy Must have recovered from toxicity of prior chemotherapy with laboratory values as specified above. Concurrent treatment with bisphosphonates is permitted. Performance status of ECOG 0-1.

Life expectancy of at least 12 weeks. At least 3 weeks since major surgical procedures. Able to swallow and retain oral medication.

Exclusion Criteria:

Pregnant or breast feeding. Known allergy to capecitabine or 5-fluorouracil. Known to have dihydropyrimidine dehydrogenase (DPD) deficiency.

Patients who have leptomeningeal carcinomatosis as the only site of CNS metastases.

Patients taking concomitant medications which are CYP3A4 inhibitors or inducers.

Patients who will receive intrathecal chemotherapy for leptomeningeal disease. Patients with psychiatric or addictive disorders that would adversely effect compliance with oral medication.

Life expectancy less than 3 months. Symptomatic lymphangitic spread to lung. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel.

History of immediate or delayed hypersensitivity reaction to gadolinium contrast agents, or other contraindication or gadolinium contrast.

Other known contraindication to MRI, such as a cardiac pacemaker, implanted cardiac defibrillator, brain aneurysm clips, cochlear implant, ocular foreign body, or shrapnel,

1Vascular disease within 12 months prior to enrollment Uncontrolled infection History of other malignancy, except for curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. Subjects with other malignancies who have been disease-free for at least 5 years are eligible

12 patients were enrolled and started treatment