This randomized, two-arm study will evaluate the efficacy and safety of a combination of trastuzumab and capecitabine with or without pertuzumab in patients with HER2-positive metastatic breast cancer. The study population consists of female patients, whose disease has progressed during or following previous trastuzumab therapy for metastatic disease. All patients in Arm A and Arm B are to receive trastuzumab (8 mg/kg iv as loading dose and then 6 mg/kg iv every 3 weeks thereafter). Patients in Arm A and Arm B are to receive capecitabine oral twice daily for 14 days every 3 weeks (1250 mg/m2 twice daily in Arm A and 1000 mg/m2 twice daily in Arm B). In addition, patients in Arm B will receive pertuzumab (840 mg iv as loading dose and then 420 mg iv thereafter) every 3 weeks. Study treatment is to continue until disease progression or unacceptable toxicity. The target sample size is 450 patients.

• Drug: pertuzumab
  pertuzumab 840 mg iv loading, then 420 mg iv every 3 weeks
• Drug: capecitabine
  capecitabine 1250 mg/m2 (Arm A) 1000 mg/m2 (Arm B) po twice daily for 14 days every 3 weeks
  Other Name: Xeloda
• Drug: trastuzumab
  trastuzumab 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks
  Other Name: Herceptin

• A: Active Comparator
  Interventions:

  • Drug: capecitabine
  • Drug: trastuzumab
• B: Experimental
  Interventions:

  • Drug: pertuzumab
  • Drug: capecitabine
  • Drug: trastuzumab

Inclusion Criteria:

• Adult patients >/=18 years of age
• Metastatic HER2 positive breast cancer
• ECOG performance status 0 or 1
• Disease progression during or following trastuzumab-based therapy for 1st line metastatic breast cancer (trastuzumab must have been part of the last prior treatment regimen)
• Prior treatment with taxane-containing regimen
• LVEF >/=50 percent
• For women of childbearing potential agreement to use highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by patient and/or partner. Contraception must continue for duration of study treatment and for at least 6 months after last dose of study drug treatment

Exclusion Criteria:

• Prior treatment with pertuzumab or capecitabine
• Concurrent treatment with other experimental drug
• Concurrent immunotherapy or anticancer hormonal therapy
• Serious concurrent disease (e.g. active infection, uncontrolled hypertension, cardiovascular disease)
• CNS metastases, which are not well controlled
• History of exposure to anthracycline cumulative dose equivalent to 360mg/m2 doxorubicin
• History of congestive heart failure of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment
• History of myocardial infarction within 6 months prior to randomization
• History of LVEF decline to below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab