Statement: Patients with Grade III peripheral neuropathy or above are eliminated from participation in the primary trial.
Primary_evidence: Inclusion Criteria:   Histologically documented, incurable, locally advanced or metastatic breast cancer   Evaluable or measurable HER2-positive disease   History of progression during or within 60 days after treatment with any prior trastuzumab-containing chemotherapy regimen for HER2-positive breast cancer   Previous treatment with chemotherapy for MBC   Granulocyte count  1,500/μL, platelet count  100,000/μL, and hemoglobin  9 g/dL   Serum bilirubin  1.5 mg/dL; AST, ALT, and alkaline phosphatase  2.5 × upper limit of normal (ULN) except for: Patients with hepatic metastases: ALT and AST  5 × ULN Patients with hepatic and/or bone metastases: alkaline phosphatase  5 × ULN   Serum creatinine  1.5 mg/dL or creatinine clearance of  60 mL/min based on a 24-hour urine collection   Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2   Women of childbearing potential and men must agree to use an effective method of birth control (e.g., hormonal, barrier) while receiving study treatment Exclusion Criteria:   History of significant cardiac disease, unstable angina, CHF, myocardial infarction, or ventricular arrhythmia requiring medication   History of Grade  3 hypersensitivity reaction to trastuzumab   History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued   Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first study treatment   Require supplemental oxygen for daily activities   Grade  2 peripheral neuropathy   Bisphosphonate therapy for symptomatic hypercalcemia   Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy for the treatment of breast cancer within 4 weeks of first study treatment   Any experimental therapy within 4 weeks of first study treatment   Any major surgical procedure within 4 weeks of first study treatment   History of clinically symptomatic liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis   Pregnancy or lactation   Cardiac troponin I  0.2 ng/mL   Ejection fraction < 50% or below the lower limit of normal determined by echocardiogram or MUGA scan   Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent