Bevacizumab and Paclitaxel or Bevacizumab, Cyclophosphamide, and Capecitabine as First-Line Therapy in Treating Women With Locally Advanced, Recurrent, or Metastatic Breast Cancer

• Objective response [ Time Frame: the best response under trial treatment ] [ Designated as safety issue: No ]
• Disease control [ Time Frame: best response under trial treatment ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: from randomization until documented tumor progression ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: the time from randomization to death from any cause ] [ Designated as safety issue: No ]
• Time to specific grade 3-5 adverse events [ Time Frame: Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint. ] [ Designated as safety issue: Yes ]

• Objective response [ Designated as safety issue: No ]
• Disease control [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Time to specific grade 3-5 adverse events [ Designated as safety issue: Yes ]
• Any adverse event (hematological adverse events of 2 or less are excluded) [ Designated as safety issue: Yes ]
• Patients who have experienced at least one adverse event of grade 3 or greater [ Designated as safety issue: Yes ]
• Any delay and/or dose reduction [ Designated as safety issue: No ]
• Quality of life [ Designated as safety issue: No ]

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether bevacizumab is more effective when given together with paclitaxel or cyclophosphamide and capecitabine in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying the side effects of giving bevacizumab together with paclitaxel and to see how well it works compared with giving bevacizumab together with cyclophosphamide and capecitabine as first-line therapy in treating women with locally advanced, recurrent, or metastatic breast cancer.

OBJECTIVES:

• To determine if bevacizumab and paclitaxel versus bevacizumab, metronomic cyclophosphamide, and capecitabine as first-line therapy causes less medication-related adverse events in women with HER2-negative metastatic, locally advanced, or recurrent breast cancer.
• To compare quality of life (QOL) in patients treated with these regimens.
• To replicate previous findings of better QOL in patients with complete response or partial response versus stable disease for 6 months or greater.
• To determine the predictive value of baseline QOL for the duration of a meaningful change in QOL of patients treated with chemotherapy.
• To determine the associations between the QOL endpoints, selected health economics, and clinical endpoints.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor response (measurable vs evaluable disease), WHO performance status (0 or 1 vs 2), and center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and paclitaxel IV on days 1, 8, and 15. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral cyclophosphamide once daily on days 1-28, and oral capecitabine 3 times a day on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients complete quality-of-life questionnaire (BL-QA) and health economics questionnaires (BL-HEA and EQ-5D) at baseline, during, and after completion of study therapy.

After completion of study treatment, patients are followed up at 1 month, every 3 months for 1 year, and then every 6 months for 1 year.

• Biological: bevacizumab, Paclitaxel
  Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle.
  Other Name: Avastin
• Biological: Bevacizumab, Cyclophosphamide, Capecitabine
  Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily
  Other Names:

  • Avastin
  • Xeloda

• Active Comparator: Arm A: bevacizumab and paclitaxel
  Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle. Both medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug is given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion.
  Intervention: Biological: bevacizumab, Paclitaxel
• Active Comparator: Arm B: bevacizumab, cyclophosphamide and capecitabine
  Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily. All three medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug(s) is (are) given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion
  Intervention: Biological: Bevacizumab, Cyclophosphamide, Capecitabine

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