2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab

First-line treatment of patients with locally recurrent or metastatic, HER2-negative breast cancer who have not received prior chemotherapy for locally recurrent or metastatic disease.

Arm A:

Bevacizumab 10 mg/kg intravenous (i.v.), days 1 and 15, every 4 weeks

Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks

Arm B:

Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks

Capecitabine 1000 mg/m² twice-daily, days 1-14, every 3 weeks

In both arms treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent.

For patients who stop chemotherapy for any reason before PD (e.g. toxicity) the other treatment should be given as monotherapy until PD.

• Biological: Bevacizumab and Paclitaxel
  A: Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks
• Biological: Bevacizumab and Capecitabine
  B:Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks

• Active Comparator: A

  Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks

  In both arms, treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent.

  Intervention: Biological: Bevacizumab and Paclitaxel
• Active Comparator: B

  Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks

  In both arms, treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent.

  Intervention: Biological: Bevacizumab and Capecitabine

• Written informed consent
• Age ≥18 years
• Able to comply with the protocol
• Histologically or cytologically confirmed, HER2-negative, adenocarcinoma of the breast with measurable or non-measurable locally recurrent or metastatic disease
• ECOG performance status of 0-2
• Life expectancy more than 12 weeks
• Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was more than 6 months prior to randomization, if (neo)adjuvant Therapy was Taxane-based, patients are eligible only if they received their last taxane more than 12 months prior to randomization.
• Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer If the last fraction of radiotherapy occurred at least 6 months prior to randomization. Radiotherapy administered solely for the relief of metastatic bone pain is allowed prior to study entry, the last fraction of radiotherapy was administered ≥ 3 weeks prior to randomization.
• Adequate left ventricular ejection function
• Adequate hematological function
• Adequate liver function
• Adequate renal function
• The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization

Exclusion Criteria:

• Previous chemotherapy for metastatic or locally recurrent breast cancer
• Concomitant hormonal therapy for locally recurrent or metastatic disease. Previous hormonal therapy must have been discontinued at least 3 weeks prior to randomization
• Previous radiotherapy for the treatment of metastatic disease
• Other primary tumors within the last 5 years, except for adequately controlled basal cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Pre-existing peripheral neuropathy NCI CTCAE grade > 2 at randomization.
• Evidence of spinal cord compression or current evidence of CNS
• History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures)
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment
• Minor surgical procedures, including insertion of an indwelling catheter, within 24 hours prior to randomization
• Current or recent (within 10 days of first dose of bevacizumab) use of aspirin or clopidogrel
• Chronic daily treatment with History or evidence of inherited bleeding diathesis or coagulopathy
• Uncontrolled hypertension
• Clinically significant cardiovascular disease, requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication.
• Non-healing wound, active peptic ulcer or bone fracture
• History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization
• Active infection requiring i.v. antibiotics at randomization.
• Pregnant or lactating females, Women of childbearing potential,not using contraception
• Men who do not agree to use contraception
• Current or recent (within 28 days of randomization) treatment with another investigational drug or participation in another investigational study
• Clinically significant malabsorption syndrome or inability to take oral medication
• Psychiatric disability
• Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug
• Known DPD deficiency or prior unanticipated severe reaction to fluoropyrimidine therapy
• Known hypersensitivity to any of the study drugs or excipients