Brain Mets - Capecitabine Plus Sunitinib and WBRT

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.