2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Bevacizumab and Paclitaxel; Bevacizumab and Capecitabine
Intervention description: 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; 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
Intervention MeSH terms: Paclitaxel; Bevacizumab; Capecitabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 564.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria

          1. Written informed consent obtained prior to any study-specific procedure.

          2. Age ≥18 years.

          3. Able to comply with the protocol.

          4. Histologically or cytologically confirmed, HER2-negative, adenocarcinoma of the breast
             with measurable or non-measurable locally recurrent or metastatic disease, who are
             candidates for chemotherapy. Locally recurrent disease must not be amenable to
             radiotherapy or resection with curative intent.

          5. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) of 0-2.

          6. Life expectancy more than 12 weeks.

          7. Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of
             chemotherapy was more than 6 months prior to randomization. However, if (neo)adjuvant
             chemotherapy was:

               -  Taxane-based, patients are eligible only if they received their last taxane more
                  than 12 months prior to randomization.

               -  Anthracycline-based, the maximum cumulative dose of prior anthracycline therapy
                  must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.

          8. Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer
             provided that 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, providing that:

               -  no more than 30% of marrow-bearing bone was irradiated

               -  the last fraction of radiotherapy was administered ≥ 3 weeks prior to
                  randomization.

          9. Adequate left ventricular ejection function (LVEF) at baseline, defined as LVEF ≥ 50%
             by either echocardiogram or multigated acquisition scan (MUGA).

         10. Adequate hematological function

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed this level).

         11. Adequate liver function

               -  Total bilirubin ≤ 1.25 x upper normal limit (ULN)

               -  Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) < 2.5 x ULN in
                  patients without liver metastases; < 5.0 x ULN in patients with liver metastases.

         12. Adequate renal function

               -  Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance ≥ 50 mL/min.

               -  Urine dipstick for proteinuria < +2. Patients discovered to have ≥ +2 proteinuria
                  on dipstick urinalysis at baseline should undergo a 24-hour urine collection and
                  must demonstrate ≤ 1g of protein in 24 hours

         13. 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

               -  Patients on heparin treatment should have a baseline activated partial
                  thromboplastin time (aPTT) between 1.5 - 2.5 times ULN or patients value before
                  starting heparin treatment

               -  Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5
                  - 2 mg/kg (of enoxaparin) or appropriate doses of the correspondent
                  anticoagulant, according to package insert

               -  Patients on coumarin derivatives should have an international normalized ratio
                  (INR) between 2.0 and 3.0 assessed at baseline in two consecutive measurements
                  1-4 days apart

               -  Patients not receiving anticoagulant medication must have an INR ≤ 1.5 and aPTT ≤
                  1.5 times ULN within 7 days prior to randomization

        Exclusion Criteria

          1. Previous chemotherapy for metastatic or locally recurrent breast cancer.

          2. Concomitant hormonal therapy for locally recurrent or metastatic disease. Note:
             previous hormonal therapy is allowed for adjuvant, locally recurrent or metastatic
             breast cancer, but must have been discontinued at least 3 weeks prior to
             randomization.

          3. Previous radiotherapy for the treatment of metastatic disease (unless given for the
             relief of metastatic bone pain and with the precautions mentioned above).

          4. Other primary tumors within the last 5 years, except for adequately controlled limited
             basal cell carcinoma of the skin, or carcinoma in situ of the cervix.

          5. Pre-existing peripheral neuropathy NCI CTCAE grade > 2 at randomization.

          6. Evidence of spinal cord compression or current evidence of central nervous system
             (CNS) metastases (even if previously treated). If suspected, the patient should be
             scanned by CT or magnetic resonance imaging (MRI) within 28 days prior to
             randomization to rule out spinal / CNS metastases.

          7. History or evidence upon physical/neurological examination of CNS disease unrelated to
             cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled
             seizures).

          8. 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.

          9. Minor surgical procedures, including insertion of an indwelling catheter, within 24
             hours prior to randomization.

         10. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325
             mg/day) or clopidogrel (> 75 mg/day).

         11. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone
             equivalent) (excluding inhaled steroids).

         12. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of
             bleeding.

         13. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg).

         14. Clinically significant (i.e. active) cardiovascular disease, requiring medication
             during the study and might interfere with regularity of the study treatment, or not
             controlled by medication.

         15. Non-healing wound, active peptic ulcer or bone fracture.

         16. History of abdominal fistula, or any grade 4 non-gastrointestinal fistula,
             gastrointestinal perforation or intra-abdominal abscess within 6 months of
             randomization.

         17. Active infection requiring i.v. antibiotics at randomization.

         18. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior
             to study treatment start, or within 14 days with a confirmatory urine pregnancy test
             within 7 days prior to study treatment start.

         19. Women of childbearing potential (< 2 years after the last menstruation) not using
             effective, non-hormonal means of contraception (intrauterine contraceptive device,
             barrier method of contraception in conjunction with spermicidal jelly or surgically
             sterile) during the study and for a period of 6 months following the last
             administration of study drug.

         20. Men who do not agree to use effective contraception during the study and for a period
             of 6 months following the last administration of study drug.

         21. Current or recent (within 28 days of randomization) treatment with another
             investigational drug or participation in another investigational study

         22. Clinically significant malabsorption syndrome or inability to take oral medication.

         23. Psychiatric disability judged by the Investigator to be interfering with compliance
             for oral drug intake.

         24. Requirement for concurrent use of the antiviral agent sorivudine or chemically related
             analogues, such as brivudine.

         25. 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, or that
             may affect patient compliance with study routines, or places the patient at high risk
             from treatment related complications.

         26. Known Dihydropyrimidine Dehydrogenase (DPD) deficiency or prior unanticipated severe
             reaction to fluoropyrimidine therapy (with or without documented DPD deficiency)

         27. Known hypersensitivity to any of the study drugs (including 5-FU) or excipients.
             Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or
             humanized antibodies. History of hypersensitivity reactions with drugs formulated in
             Cremophor® EL (polyoxyethylated castor oil), or previous therapy with bevacizumab.