Investigational Drug in Combination With Two Chemotherapy Drugs in Women With Locally Recurrent or Metastatic Breast Cancer

Inclusion Criteria: * Histologically or cytologically confirmed adenocarcinoma of the breast regardless of ER, PR and Her2 status with locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent. * Disease progression after at least 1, but no more than 2, prior chemotherapy regimens for metastatic disease. * Patients with hormone-sensitive tumors must have received prior hormonal therapy and not be amenable to further hormonal therapy. * Patients with HER2/neu-overexpressing tumors (3+ by immunohistochemistry or amplified by fluorescent in situ hybridization) should have received trastuzumab (Herceptin®) and/or lapatinib (Tykerb®) in the adjuvant or metastatic setting (unless contraindicated) and have progressed while on treatment of metastatic disease or within 12 months of completion of adjuvant therapy. * Patients will eligible if they have tumors that express one of the motesanib-directed tyrosine kinase markers, the target markers:(PDGFR, VEGFR, c-Kit) as determined by study pathologist. Immunohistochemical assays for these markers are provided by grant consortium partner and CLIA-certified diagnostics laboratory MDRG. * Measurable disease per RECIST (Response Evaluation Criteria in Solid Tumor) guidelines. * Complete radiology and tumor measurement within 4 weeks (28 days) prior to enrollment. * Chest: CT scan with intravenous contrast if the contrast is not medically contraindicated. * Abdomen: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated. * Pelvis: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated. * Brain: CT scan or MRI * Bone: Whole body Bone Scintigraphy or PET scan * Female 18 years of age or older at the time the written informed consent is obtained. * ECOG Performance Status of 0 or 1. * Adequate organ and hematological function as evidenced by the following laboratory studies within 2 weeks (14 days) of study enrollment, unless stated otherwise: * Cardiac function, as follows: * Normal sinus rhythm (no significant ECG changes) * Left ventricular ejection fraction ≥ Lower Limit of Normal, as determined by echocardiogram or MUGA scan, according to institutional standards within 28 days prior to study enrollment. * Hematological function, as follows: * Absolute neutrophil count ≥ 1.5 x 109/L * Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L * Hemoglobin ≥ 9 g/dL. * PTT and INR \< 1.5 x ULN. * Renal function, as follows: * Serum creatinine ≤ 175 µmol/L (= 2mg/dL). If creatinine is between 140-175 µmol/L, creatinine clearance (calculated or measured) should be \> 40 mL/min. * Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤ 1 + on dipstick unless protein is \< 500 mg in a 24-hour urine sample. * Hepatic function, as follows: * Aspartate aminotransferase (AST) ≤ 2.5 x ULN * Alanine aminotransferase (ALT) ≤ 2.5 x ULN * Total bilirubin ≤ 1 x ULN * Patients of child-bearing potential and sexually active must provide a negative pregnancy test within 7 days prior to enrollment. * More than 4 weeks since prior therapy for breast cancer * No other concurrent investigational or commercial agents or therapies for metastatic breast cancer * No prior capecitabine or fluorouracil for metastatic breast cancer * More than 4 weeks since prior radiotherapy \*\*Previously irradiated area(s) must not be the only site of disease\*\* * More than 4 weeks since prior major surgery Exclusion Criteria: Disease Related: * Current or prior history of central nervous system metastasis. * Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 peripheral neuropathy ≥ grade 2 at enrollment. * Average systolic blood pressure \> 150 mm Hg or average diastolic blood pressure \> 90 mm Hg (average blood pressure of the 3 separate blood pressure values measured according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. * History of arterial or venous thrombosis within 1 year prior to enrollment. * History of bleeding diathesis or bleeding within 14 days of enrollment. * Major surgical procedure within 4 weeks (28 days) prior to enrollment. * Minor surgical procedure, placement of access device, or fine needle aspiration within 7 days of enrollment. * Known positive test for human immunodeficiency virus (HIV), hepatitis C, or malignancy (other than in situ cervical cancer, or basal cell cancer of the skin), unless treated with curative intent and without evidence of disease for ≥ 3 years before study enrollment. * Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade II or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or ongoing arrhythmias requiring medication or pacemaker. * Non-healing wound, ulcer or fracture. * Ongoing or active infection. * Known chronic hepatitis. Medications: * Currently or previously treated with small molecule inhibitors of VEGF including, but not limited to, SU11248 (sunitinib), PTK787 (vatalinib), AZD 2171, AZD 6474, AEE-788, BAY 43-9006 (sorafenib) and motesanib. * Treatment with rifampin, carbamazepine, rifabutin or phenobarbital within 14 days prior to study enrollment. * Treatment with strong CYP 3A inhibitors or inducers such as ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, nefazodone, or any HIV protease inhibitors within 7 days prior to study enrollment. * Treatment with immune modulators such as cyclosporine and tacrolimus within 7 days prior to study enrollment. * Treatment with herbal medications containing St. John's Wort within 7 days prior to study enrollment. * Concomitant therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMS), given for breast cancer prevention or for osteoporosis. Patients must have discontinued these agents prior to enrollment. General: * Known hypersensitivity to any study medications (motesanib, and Chinese Hamster Ovary cell products or other human or humanized recombinant proteins) or Cremaphor. * Any condition which in the investigator's opinion makes the patient unsuitable for the study participation. This includes substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. * Participation in other investigational device drug trials, or administration of other investigational treatments within 30 days prior to study enrollment. * Pregnant (i.e., positive beta-human chorionic gonadotropin test) * Not willing to use a highly effective method of birth control (i.e. those which result in low failure rates, less than 1% per year), such as nonhormonal IUD, condoms, sexual abstinence or vasectomised partner. \*\*Contraception must be used during the study and for 6 months after last dose of study treatment\*\* * Unable to swallow oral medications. * Inability to comply with protocol and/or not available for follow-up assessments. * Males of any age.