This is a phase l/II study. The purpose of this study is to test the safety of the study drug neratinib in combination with a standard chemotherapy drug called capecitabine at different doses to find out what effects, if any, it has on people. Capecitabine (Xeloda®) is approved by the Food and Drug Administration (FDA) for advanced breast cancer treatment. Neratinib is an investigational drug, meaning the FDA has not approved the use of this drug for advanced breast cancer. The combination of capecitabine and neratinib has been studied before in another study where capecitabine was administered using the standard dosing schedule. In this study, the investigators want to find out if a different dosing schedule of capecitabine combined with neratinib is safer. This different dosing schedule is experimental, meaning the administration schedule of capecitabine and neratinib is not FDA approved for treatment for HER2 positive advanced breast cancer.

Inclusion Criteria:

• Aged ≥18 years at signing of informed consent.
• Histologically confirmed MBC, current stage IV.
• Documented HER2 overexpression (immunohistochemistry (IHC) 3+ or gene-amplified tumor with fluorescence in situ hybridization (FISH) ratio of ≥ 2.0.
• For phase Ib, any line of prior treatments is permitted including prior neratinib and capecitabine.
• For phase II, up to 4 prior chemotherapy-based treatments in the metastatic setting are allowed. Patients must have had prior trastuzumab-based therapy. Prior neratinib treatment is not permitted. Prior capecitabine is allowed, if not combined with neratinib.
• Measurable or non-measurable disease is permitted as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) for phase 1b. For phase 2, patients must have measurable disease as defined in RECIST v1.1.
• Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
• Eastern Cooperative Oncology Group (ECOG) status of 0 to 1
• Hematologic parameters: white blood cell (WBC) count of > 3000/ul, absolute neutrophil count (ANC) ≥ 1000/ul, platelets ≥ 50,000/ul, hemoglobin ≥ 8.0 g/dl
• Non-hematologic parameters: bilirubin ≤ 1.5 mg/dl, AST/ALT ≤ 3.0 x upper limit of normal (ULN) (≤ 5.0 x ULN if liver metastases are involved)
• Creatinine ≤1.5 mg/dl Patients with "treated and stable" brain lesions of a duration of ≥ 2 months may be enrolled.
• Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
• Women of childbearing potential must agree and commit to the use of a highly effective method of contraception as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of the investigational product. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after last dose of investigational products.
• Provide written, informed consent to participate in the study and follow the study procedures

Exclusion Criteria:

• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia
• Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m^2 doxorubicin.
• Any major surgery ≤28 days prior to the initiation of investigational products, or received anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer therapy) administered ≤14 days prior to the initiation of investigational products.
• Received radiation therapy ≤14 days prior to initiation of investigational products.
• QTc interval >450 ms for men or 470 ms for women, or known history of QTc prolongation or Torsades de Pointes.
• Active hepatitis B or C
• Active infection or unexplained fever >38.5°C (>101.3°F) within 2 weeks prior to enrollment.
• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 diarrhea of any etiology screening).
• Known dihydropyrimidine dehydrogenase deficiency.
• Known hypersensitivity to 5-fluorouracil or to any component of the investigational products or compounds of similar chemical composition.
• Pregnant patients or currently breast-feeding.

Breast Cancer