A Multicenter Randomized Phase III Study to Compare Capecitabine Alone or in Combination With Trastuzumab in Patients With HER2 Positive Metastatic Breast Cancer and Progression After Previous Treatment With Trastuzumab
1. Written informed consent prior to beginning specific protocol procedures, including
expected cooperation of the patients for the treatment and follow-up, must be
obtained and documented according to the local regulatory requirements.
2. Pathologically confirmed carcinoma of the breast.
3. Locally advanced or metastatic stage of disease not suitable for surgery or
4. HER2-overexpression of the primary or metastatic tumor tissue detected by
immunohistochemistry (DAKO) 3+ or gene namplification detected by FISH. HER2-positive
primary tumours with HER2-negative metastasis can be included.
5. Disease progression during or after previous chemotherapy and trastuzumab treatment
as follows (Trastuzumab has to be given previously for at least 12 weeks, treatment
free interval of trastuzumab for a maximum of 6 weeks):
- Taxanes + trastuzumab given as adjuvant therapy
- Taxanes + trastuzumab given as first line therapy for palliation
- Trastuzumab given as first line therapy for palliation alone or in combination
with chemotherapeutic agents other than capecitabine or taxanes
6. No more than 1 chemotherapy for palliation (max. Adriamycin dose < or = 400 mg/m²;
Epirubicin < or = 600 mg/m²)
7. Patients must have either measurable or nonmeasurable target lesions according to the
RECIST criteria (see Appendix 6)
8. At least 4 weeks since radiotherapy, with full recovery. The measurable disease must
be completely outside the radiation portal or there must be pathologic proof of
9. At least 4 weeks since major surgery with full recovery.
10. Complete radiology and tumor measurement work up within 4 weeks prior to
11. Karnofsky performance status evaluation > or = 60%
12. Age >18 years.
13. Absolute neutrophil count > or =1,500 cells/microL, platelet count > or =100,000
14. Bilirubin < or = 2x the upper limit of normal for the institution (ULN); elevation of
transaminases and alkaline phosphatase < 2.5x ULN or <5x ULN for patients with liver
15. Creatinine < or = 2.0 mg/dl.
16. Left ventricular ejection fraction (LVEF) by cardiac ultrasound of > or = 50%.
17. If of childbearing potential, pregnancy test is negative. In addition the patient
agrees to use an effective method to avoid pregnancy for the duration of the study.
1. Known hypersensitivity reaction to the compounds or incorporated substances or known
dihydropyrimidine dehydrogenase deficiency.
2. Concurrent immunotherapy or hormonal therapy (antihormonal, contraceptive and/or
replacement therapy). Bisphosphonates may be continued.
3. Parenchymal brain metastases, unless adequately controlled by surgery and/or
radiotherapy with complete resolution of symptoms and of all steroids.
4. Life expectancy of less than 3 months.
5. Serious intercurrent medical or psychiatric illness that may interfere with the
planned treatment (including severe pulmonary conditions, AIDS and serious active
6. History of congestive heart failure or other significant uncontrolled cardiac
7. History of other malignancy within the last 5 years which could affect the diagnosis
or assessment of breast cancer.
8. Concurrent treatment with other experimental drugs. Participation in another clinical
trial with any investigational not marketed drug within 30 days prior to study entry.
9. Treatment with sorivudine or derivates e.g. brivudin
10. Pregnant or nursing women.
11. Male patients.
12. The patient must be accessible for treatment and follow-up. Patients registered on
this trial must be treated and followed at the participating centre which could be
the Principal or Co- investigator's site.