change in development plan, not due to safety concerns.

This study has the purpose to demonstrate clinical efficacy of the investigational new drug ertumaxomab in patients with human epidermal growth factor receptor-2 (HER-2/neu) overexpressing (3+ or 2+ with a positive Fluorescence In Situ Hybridization (FISH) test result) metastatic breast cancer progressing after trastuzumab treatment.

Ertumaxomab is a trifunctional bispecific antibody targeting Her-2/neu on tumor cells and CD3 on T cells. Trifunctional antibodies represent a new concept for targeted anticancer therapy. This new antibody class has the capability to redirect T cells and accessory immune effector cells (e.g. macrophages, dendritic cells [DCs] and natural killer [NK] cells) to the tumor site. According to preclinical data, trifunctional antibodies activate these immune cells, which can trigger a complex anti-tumor immune response.

This study is an open-label, non-randomized, uncontrolled, two-stage phase II study evaluating the efficacy and safety of ertumaxomab. Ertumaxomab will be administered three times at 7 day intervals by constant rate 3 hour intravenous (i.v.) infusions according to the following dose schedule: 10 µg (day 0); 100 µg (day 7 ± 1 day) and 100 µg (day 14 ± 1 day) (flat doses).

Key Inclusion Criteria:

• Women ≥ 18 years, Negative pregnancy test at screening and life expectancy of at least 3 months
• metastatic (stage IV) and not curable adenocarcinoma of the breast
• Measurable disease, defined as at least one lesion that is measurable in one dimension (RECIST)
• HER-2 overexpression 3+ or 2+ FISH positive
• Patients must have received one prior therapy with trastuzumab as last treatment before entry into the study. If trastuzumab was given as single agent treatment, patients must have received prior chemotherapy for metastatic disease
• Trastuzumab has been discontinued before study entry
• disease had progressed during or after trastuzumab therapy
• Eastern Cooperative Oncology Group (ECOG)performance score of ≤ 2
• Adequate hematological, liver and kidney function

Key Exclusion Criteria:

• Women who are pregnant or breast feeding
• Any history or symptoms indicative of brain or central nervous system metastases
• Prior diagnosis of any malignancy not cured by surgery alone less than 5 years before study entry (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin)
• Human anti-murine antibody positive or hypersensitivity to murine proteins and any other component of the study drug
• Known autoimmune diseases, Human immunodeficiency virus (HIV), hepatitis B or C infection as well as other acute or chronic infection or other concurrent non-malignant co-morbidities that are uncontrolled
• Any concurrent chemotherapy, hormonal therapy, immunotherapy or corticoid therapy
• Concurrent antibiotic treatment
• Any concurrent investigational treatment for metastatic disease

Cardiovascular exclusion criteria:

• Unstable or uncontrolled pectorial angina
• Myocardial infarction during the last 6 months
• Valvular heart disease that requires treatment
• Cardiomyopathy (congestive, hypertrophic or restrictive)
• Acute myocarditis
• Congestive heart failure (CHF): dyspnea, clinically or radiologically diagnosed
• Left ventricular ejection fraction (LVEF)outside institution's normal range based on echocardiography at rest
• Left ventricular diameter > 56 mm based on M-mode echocardiography at rest
• Arrhythmias that require treatment (atrioventricular block II/III degree, atrial fibrillation, ventricular tachycardia)
• Poorly or uncontrolled hypertension, asthma, seizures, allergies, pulmonary dysfunction

The Site may publish the results of the Study after such cooperative publication, or 1 year after Sponsor's final evaluation of all the Study data from all sites, whichever occurs first. Prior to any submission for publication, presentation, or communication of results or information arising from the Study, Investigator shall provide Fresenius Biotech at least 90 days for review and comment upon the manuscript or other material for such publication or presentation.