Phase II Trial to Validate Markers for a Response Evaluation of a Combined Therapy in Patients With HER2+ Breast Cancer

Inclusion Criteria:

1. Female patients, age at diagnosis 18 - 75 years
2. Histological confirmed unilateral primary invasive carcinoma of the breast
3. Clinical Stage Tumor 1 (cT1) (> 1 cm) - Clinical Stage Tumor 4 (cT4) (if operable, inflammatory breast cancer is excluded)
4. HER2 over-expressing tumor confirmed by: 3+ by Immuno-histochemistry (IHC) and/or HER2/neu gene amplification by fluorescence, chromogenic or silver in-situ hybridization [Fluorescent In-Situ Hybridization (FISH), Chromogenic In-Situ Hybridization (CISH) or Silver In-Situ Hybridization (SISH); > 6 HER2 gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥ 2.0]
5. Clinically node positive disease or node negative disease
6. No clinical evidence for distant metastasis (cM0) after conventional staging
7. Performance Status Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky Index (KI) ≥ 80%
8. Baseline Left Ventricular Ejection Fraction (LVEF) > 50% measured by echocardiography
9. Negative pregnancy test (urine or serum) within 7 days prior to start of induction treatment in premenopausal patients
10. The patient must be accessible for treatment and follow-up
11. Written informed consent including a written informed consent for shipping of tumor block for central pathology review and evaluation prior to the start of any study procedures

Exclusion Criteria:

1. Known hypersensitivity reaction to the compounds or incorporated substances
2. Known polyneuropathy grade ≥ 2
3. Have acute or currently active or requiring anti-viral therapy hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment).
4. Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
5. Prior or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
6. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry
7. Male breast cancer
8. Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
9. Breast feeding women
10. Sequential breast cancer
11. Lack of patient compliance

12. Inadequate organ function including:

    • Leucocytes < 3.5 x 109/l
    • Platelets < 100 x 109/l
    • Absolute Neutrophil Count (ANC) < 1.5 x 109/l
    • Hemoglobin < 9 g/dl
    • Serum Creatinine > 1.5 mg/dl
    • Serum Bilirubin > 1.1 mg/dl
    • Alkaline phosphatase > 2.5 x Upper Limit of Normal (ULN)
    • Aspartate Transaminase (ASAT) and/or Alanine Transaminase (ALAT) > 2.5 ULN
    • Albumin < 2.5 g/dl
13. Uncompensated cardiac function
14. Malabsorption syndrome, disease significantly affecting gastrointestinal function
15. Concomitant use of Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers