A Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 4,994
- 试验地点
- 1,691
- 主要终点
- Invasive Disease-free Survival (IDFS) Rate at 5 Years
研究概览
简要总结
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, and paclitaxel to see how well they work with or without bevacizumab in treating patients with cancer that has spread to the lymph nodes (lymph node-positive) or cancer that has not spread to the lymph nodes but is at high risk for returning (high-risk, lymph node-negative breast cancer). Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery and help prevent the tumor from returning. It is not yet known whether doxorubicin hydrochloride, cyclophosphamide, and paclitaxel are more effective with or without bevacizumab.
详细描述
PRIMARY OBJECTIVES:
I. To determine the disease-free survival of patients (defined as invasive disease-free survival [IFDS]) with lymph node positive and high risk lymph node negative breast cancer randomized to treatment with either doxorubicin (doxorubicin hydrochloride)/cyclophosphamide plus placebo followed by paclitaxel (AC + placebo > T + placebo) or the same chemotherapy regimen plus bevacizumab.
SECONDARY OBJECTIVES:
I. To compare short-term (20-24 weeks) versus long-term (50-54 weeks) bevacizumab therapy.
II. To compare the overall survival. III. To evaluate toxicity. IV. To evaluate the association between outcomes in E5103 (disease-free survival, overall survival and toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome wide evaluations).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed adenocarcinoma of the breast at significant risk of distant recurrence based on at least one of the following criteria:
- •For axillary lymph node positive disease:
- •Involvement of at least one sentinel or axillary lymph node on routine histologic examination; patients with negative sentinel nodes and negative axillary nodes or involvement only demonstrated by immunohistochemistry are not eligible unless they meet one of the other eligibility criteria below
- •NOTE: consider intramammary nodes as equivalent to axillary nodes for the purposes of eligibility and stratification
- •For axillary lymph node negative disease:
- •Estrogen receptor (ER) negative tumor >= 1 cm
- •ER+ tumor >= 5 cm regardless of recurrence score
- •ER+ tumor >= 1 cm but < 5 cm with a recurrence score >= 11 (patients enrolled in the TAILORx trial are eligible)
- •NOTE: axillary dissection is strongly encouraged in patients with lymph node involvement identified on sentinel node biopsy
- •Patients must have completed definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, breast conservation surgery and axillary dissection or breast conservation surgery and sentinel node biopsy
- •NOTE: breast conservation surgery includes lumpectomy, partial mastectomy, and excisional biopsy
- •Margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ (DCIS); patients with resection margins positive for lobular carcinoma in situ (LCIS) are eligible
- •Time from last surgery for breast cancer (breast conservation surgery, mastectomy, sentinel node biopsy, axillary dissection or re-excision of breast conservation surgery margins) to planned treatment start date must be > 28 days and =< 84 days
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Within =< 8 weeks prior to randomization: Absolute neutrophil count >= 1,000/mm^3
- •Within =< 8 weeks prior to randomization: Platelet count >= 100,000/mm^3
- •Within =< 8 weeks prior to randomization: Total bilirubin =< 1.5 mg/dL
- •Within =< 8 weeks prior to randomization: Aspartate aminotransferase (AST) =< 2 times upper limit of normal(ULN)
- •Within =< 8 weeks prior to randomization: Serum creatinine =< 1.5 mg/dL
- •Within =< 8 weeks prior to randomization: Urine protein:creatinine ratio < 1.0 or 24-hour protein
- •Within =< 8 weeks prior to randomization: Partial thromboplastin time (PTT) =< 1.5 times ULN
- •Within =< 8 weeks prior to randomization: Left ventricle ejection fraction (LVEF) >= institutional limits of normal by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
- •Patients who have undergone breast conservation surgery must receive radiation; prior to randomization, the investigator must specify the planned radiation technique:
- •Whole breast radiation (WBRT) after chemotherapy
- •Accelerated partial breast radiation (APBI) after chemotherapy
- •Accelerated partial breast radiation (APBI) prior to chemotherapy
- •NOTE: if APBI was completed prior to study entry, day 1 of protocol therapy must be at least 4 weeks after the completion of APBI
- •Post-mastectomy radiation therapy (RT) is required for all patients with a primary tumor of >= 5 cm or involvement of 4 or more lymph nodes; post-mastectomy RT may be administered at the investigator's discretion for all other mastectomy patients
- •Patients with human epidermal growth factor receptor (HER)2 + (3+ by immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] ratio >= 2) breast cancer are not eligible
- •Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher tumor, node, metastasis (TNM) stage tumor meets the eligibility criteria for this trial
- •Patients must not have clinical evidence of inflammatory disease or fixed axillary nodes at diagnosis
- •Patients must not have received prior cytotoxic chemotherapy or hormonal therapy for this breast cancer; prior treatment with an anthracycline, anthracenedione or taxane for any condition is not allowed
- •NOTE: prior use of tamoxifen for chemoprevention is allowed but must be discontinued at study entry; similarly, prior raloxifene use is allowed but must be discontinued at study entry
- •Patients must not have had any major surgical procedure within 28 days of planned treatment start date
- •NOTE: non-operative biopsy or placement of a vascular access device is not considered a major surgery
- •Patients may not have had placement of a vascular access device within 24 hours of planned day 1 of treatment
- •Patients must not have clinically significant cardiovascular or cerebrovascular disease, including:
- •Any history of
- •Cerebrovascular disease including transient ischemic attack (TIA), stroke or subarachnoid hemorrhage
- •Ischemic bowel
- •Within the last 12 months
- •Myocardial infarction
- •Unstable angina
- •New York Heart Association (NYHA) class II or greater congestive heart failure
- •Grade II or greater peripheral vascular disease
- •Uncontrolled hypertension defined as systolic blood pressure (SBP) > 160 or diastolic blood pressure (DBP) > 90
- •Uncontrolled or clinically significant arrhythmia
- •NOTE: blood pressure must be obtained within =< 8 weeks prior to randomization
- •NOTE: patients with controlled atrial fibrillation are eligible
- •Patients who require full-dose anticoagulation may enroll provided they meet the following criteria:
- 另有 8 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Paclitaxel (Drug)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Paclitaxel (Drug)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Cyclophosphamide (Drug)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Quality-of-Life Assessment (Other)
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Bevacizumab (Biological)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Cyclophosphamide (Drug)
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Quality-of-Life Assessment (Other)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Placebo Administration (Other)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Laboratory Biomarker Analysis (Other)
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Quality-of-Life Assessment (Other)
Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride IV, cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Bevacizumab (Biological)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Paclitaxel (Drug)
Arm II (chemotherapy, bevacizumab)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Invasive Disease-free Survival (IDFS) Rate at 5 Years
时间窗: Assessed at 5 years
Invasive disease-free survival (IDFS) was defined as time from from date of randomization to first treatment failure (invasive ipsilateral, local/regional, or distant recurrence, invasive contralateral breast cancer, invasive non-breast second primary malignancy or death from any cause, whichever occurred first). Cases with incomplete follow-up, without documented IDFS event including those who developed squamous or basal cell skin cancers or insitu carcinomas of any site as their only event were censored at the date of last disease evaluation.
次要结局
- 5-year Overall Survival (OS)(Assessed at 5 years)
- The Association Between IDFS and Genotype(Assessed at 3 years)