Metronomic Therapy in Metastatic Breast Cancer.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Safety and Tolerability of Bevacizumab Plus Paclitaxel vs. Bevacizumab Plus Metronomic Cyclophosphamide and Capecitabine as First-Line Therapy in Patients With HER2-Negative Metastatic or Locally Recurrent Breast Cancer - A Multicenter, Randomized Phase III Trial.

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: bevacizumab, Paclitaxel
* Biological: Bevacizumab, Cyclophosphamide, Capecitabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: bevacizumab and paclitaxel<br>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. | Biological: bevacizumab, Paclitaxel<br>* 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.<br>* Other names: Avastin;|
| Active Comparator: Arm B: bevacizumab, cyclophosphamide and capecitabine<br>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 | Biological: Bevacizumab, Cyclophosphamide, Capecitabine<br>* Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3-5 adverse events | Patients who have experienced at least one of the adverse event grade ≥ 3 according to the NCI CTCAE criteria 4.0 are considered for the primary endpoint. | Documentation of AE observed during trial treatment and in follow-up until resolution | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response (OR) | OR is the best response under trial treatment, defined as a complete response (CR) or partial response (PR) as assessed by RECIST v1.1. | the best response under trial treatment | 
| Disease control (DC) | DC is the best response under trial treatment, defined as CR + PR + stable disease. | best response under trial treatment at 24 weeks after randomization | 
| Progression-free survival (PFS) | PFS is calculated from randomization until documented tumor progression according to RECIST 1.1 or death of any cause, whichever occurs first. | from randomization until documented tumor progression | 
| Overall survival (OS) | OS is defined as the time from randomization to death from any cause | the time from randomization to death from any cause | 
| Time to specific grade 3-5 adverse events | Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint. | Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-negative breast cancer, recurrent breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer