Safety and Efficacy of Lapatinib Plus Trastuzumab or Lapatinib Plus Capecitabine in Metastatic Breast Cancer

Exclusion Criteria

• •1. Patients with confirmed brain metastases or a history of primary central nervous system tumours or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Patients with treated brain metastases that are asymptomatic and have been clinically stable for 3 months will be eligible for protocol participation.
• •2. Hormone receptor-positive patients
• •3. Prior treatment with lapatinib within the last 6 months.
• •4. More than 2 lines of trastuzumab-based treatment for advanced disease.
• •5. Significant cardiovascular disease, such as
• •* History of myocardial infarction, acute coronary syndromes (including unstable angina), or history of coronary angioplasty/stenting/bypass grafting within past 6 months.
• •* History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Classes II-IV or LVEF \<50% by ECHO.
• •* Severe cardiac arrhythmia requiring medication or severe conduction abnormalities.
• •* Poorly controlled hypertension (resting diastolic blood pressure \>100 mmHg)
• •* Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy.
• •6. QTc prolongation defined as a QTc interval \> 460 msec or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate \< 50 beats/min)
• •7. Subjects who have current active hepatic or biliary disease or severe hepatic impairment (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• •8. Malabsorption syndrome or other condition that would interfere with enteral absorption
• •9. Hypersensitivity to trastuzumab, murine proteins or to any of the excipients.
• •10. Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
• •11. History of severe and unexpected reactions to fluoropyrimidine therapy.
• •12. Hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
• •13. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• •14. Severe leucopenia, neutropenia or thrombocytopenia.
• •15. Severe renal impairment (creatinine clearance \< 40 ml/min.).
• •16. Treatment with sorivudine or its chemically related analogues, such as brivudine.
• •17. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
• •18. Contraindications to any of the medicinal products in the combination regimen.
• •19. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
• •20. Patients accommodated in a closed institution by authority or court order.
• •21. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry.