Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III 2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab for the First-line Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Locally Recurrent or Metastatic Breast Cancer
Brief 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.


Options:
A: 1. Patients with operable, histologically confirmed adenocarcinoma of the female breast.
2. TNM Stage per AJCC Cancer Staging Manual 6th edition:

   * T1-4 (Tumor size \> 1 cm), N0, M0 or T1-4, N1-3, M0
   * Patients with bilateral, synchronous breast cancer are eligible as long as one primary tumor meets the criteria above.
3. Patients with HER2/neu positive, negative or unknown disease are eligible for this trial.

   Patients whose tumors are HER2 positive by either immunohistochemistry 3+ staining or demonstrate gene amplification by FISH will be eligible to receive trastuzumab, as outlined in the protocol.
4. Age 65 years or older
5. Performance status 0-2 (Common Toxicity Criteria).
6. Prior treatment:

   * Surgical resection -

     * All tumor should be removed by either a modified radical mastectomy or a lumpectomy. Patients must be registered ≤ 84 days from mastectomy or within 84 days of axillary dissection if patient's most extensive breast surgery was a breast sparing procedure.
     * Node dissection: Axillary node dissection is not required. Management of the axilla is at the discretion of the treating physician. There is no restriction on eligibility based on the number of nodes removed.
     * Mastectomy: There should be no evidence of gross or microscopic invasive tumor at the surgical resection margins noted in the final surgery or pathology reports for patients who have had a modified radical mastectomy. Patients with close margins (tumor \< 1 mm from margin) are eligible.
     * Segmental mastectomy (lumpectomy): Although clear margins are preferable, DCIS or LCIS at the surgical resection margin will not render a patient who has undergone a segmental mastectomy ineligible for this study. Invasive tumor at the final resection margin will render a patient ineligible.
   * No prior chemotherapy for this malignancy.
   * Patients with a history of hypersensitivity to 5-FU or known dihydropyrimidine dehydrogenase (DPD) deficiency are not eligible to participate.
   * Patients may receive up to four weeks of tamoxifen therapy for this malignancy and still be eligible for study entry. Patients who received tamoxifen or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer) are eligible. Tamoxifen or raloxifene therapy should be discontinued before the patient is enrolled on this study.
7. Required Initial Laboratory Data:

   * Granulocytes \> 1,500/µl
   * Platelet count ≥100,000/µl
   * Calculated Creatinine Clearance \> 30 mL/min
   * Total bilirubin ≤ ULN
B: Inclusion Criteria:

* Female patients, \>/= 18 years of age
* Histologically confirmed HER2-negative breast cancer
* Disease progression during or following first-line treatment with Avastin and chemotherapy for locally recurrent or metastatic breast cancer
* Avastin treatment in first-line setting must have been a minimum of 4 cycles (15 mg/kg) or 6 cycles (10 mg/kg) in combination with chemotherapy
* ECOG performance status 0-2
* At least 28 days since prior radiation therapy or surgery and recovery from treatment

Exclusion Criteria:

* Anti-angiogenic therapy or anti-vascular endothelial growth factors other than Avastin for first-line treatment
* Active malignancy other than superficial basal cell and superficial squamous cell carcinoma of the skin, or in situ carcinoma of the cervix or breast within the last 5 years
* Inadequate renal function
* Clinically relevant cardio-vascular disease
* Known CNS disease except for treated brain metastases
* Chronic daily treatment with high-dose aspirin (\>325 mg/day) or clopidogrel (\>75 mg/day)
* Pregnant or lactating women
C: 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.
D: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed adenocarcinoma of the breast

  * Locally advanced, recurrent, or metastatic disease
* HER2-negative disease
* Measurable or evaluable disease
* Candidate for taxane-based chemotherapy
* No presence or history of CNS metastasis

  * Clinical suspicion of CNS metastasis must be confirmed by CT or MRI scan
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* WHO performance status 0-2
* Neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* Hemoglobin ≥ 80 g/L
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST ≤ 5 times ULN
* Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in case of liver metastases or ≤ 10 times ULN in case of bone metastases)
* Serum creatinine ≤ 1.5 times ULN
* Urine protein \< 2+ by dipstick OR ≤ 1 g by 24-hour urine collection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 12 months after completion of study therapy
* Patients with INR \> 1.5 (or Quick ≤ 70%) OR aPTT \> 1.5 times ULN within 7 days prior to expected first trial treatment must be receiving anticoagulant medication

  * Patients receiving full-dose oral or parental anticoagulants may be included in the trial provided anticoagulant dosing has been stable for at least 2 weeks prior to trial entry and the appropriate coagulation monitoring tests are within local therapeutic limits
* Must be compliant and geographically proximal for staging and follow-up
* No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
* No known hypersensitivity to trial drugs or its active compound (e.g., fluoropyrimidine), any other components of the trial drugs, or drugs formulated with cremophor EL including hypersensitivity to Chinese hamster ovary cell products or any other humanized recombinant antibodies
* No preexisting peripheral motor or sensory neuropathy \> NCI CTCAE grade 2 (i.e., moderate symptoms or limiting instrumental activities of daily living)
* No history or evidence of inherited bleeding diathesis, coagulopathy with the risk of bleeding, serious nonhealing wound, active peptic ulcer, nonhealing bone fracture, or bleeding metastases
* No history of abdominal fistula, grade 4 bowel obstruction, or gastrointestinal perforation or intra-abdominal abscess within the past 6 months
* No evidence of other medical conditions that would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs, including any of the following:

  * DPD deficiency
  * Severe respiratory, cardiac, hepatic, or renal disease
  * Active infection
  * Uncontrolled diabetes mellitus
  * Uncontrolled hypertension ≥ 140/100 mm Hg
  * Myocardial infarction within the past 12 months
  * Cerebrovascular accident or stroke within the past 6 months
  * History of hemorrhagic disorders
* No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, filling out quality-of-life forms, or interfering with compliance for oral drug intake

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for metastatic or locally recurrent breast cancer
* No prior radiotherapy for metastatic disease

  * Prior radiotherapy for the relief of metastatic bone pain allowed provided no more than 30% of marrow-bearing bone was irradiated
* At least 12 months since prior bevacizumab or other anti-VEGF therapy
* At least 12 months since prior capecitabine, continuous (\> 24 hours) fluorouracil infusion, or other oral fluoropyrimidine (e.g., eniluracil/fluorouracil, uracil/tegafur, S1, or emitefur)
* At least 12 months since prior taxane-based chemotherapy
* At least 6 months since other prior (neo)adjuvant chemotherapy
* At least 30 days since prior treatment in another clinical trial
* At least 24 hours since prior minor surgical procedures
* At least 28 days since prior and no concurrent major surgical procedures (including open biopsy) and no anticipation of the need for major surgery during the first course of this trial
* At least 10 days since prior hormone therapy for metastatic disease
* No continuous daily treatment with corticosteroid except for inhaled steroids
* No concurrent chronic daily aspirin \> 325 mg/day
* No concurrent chronic daily clopidogrel \> 75 mg/day
* No other concurrent anticancer treatments
* No other concurrent investigational treatments or experimental drugs
* No other concurrent drug therapy contraindicated for use with the trial drugs

Answer: C