Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin +/- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 454
- 试验地点
- 892
- 主要终点
- Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is).
研究概览
简要总结
This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
详细描述
PRIMARY OBJECTIVES:
I. To determine whether adding bevacizumab to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent dose-dense doxorubicin and cyclophosphamide (ddAC) significantly raises the rate of pathologic complete response (pCR) in the breast in patients with hormone receptor (HR)-poor/human epidermal growth factor receptor 2 (HER2) (-), resectable breast cancer.
II. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with HR-poor/HER2(-), resectable breast cancer.
III. To determine whether adding bevacizumab every 2 weeks to neoadjuvant weekly paclitaxel (+/- carboplatin) and subsequent ddAC significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array.
IV. To determine whether adding carboplatin every 3 weeks to neoadjuvant weekly paclitaxel followed by ddAC (+/- bevacizumab) significantly raises the rate of pCR in the breast in patients with basal-like breast cancers, as defined by gene expression array.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 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
- •Invasive breast cancer, diagnosed by core needle or incisional biopsy (excisional biopsy not permitted)
- •The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor (ER) and progesterone receptor (PgR) negative or staining present in =< 10% of invasive cancer cells by immunohistochemistry (IHC)
- •The invasive tumor must be HER2-negative, defined as IHC 0-1+ or with a fluorescent in situ hybridization (FISH) ratio (HER2 gene copy/chromosome 17) of < 2.0 if IHC 2+
- •Clinical stage II-III invasive breast cancer with intent to perform surgical resection after neoadjuvant therapy; patients with inflammatory breast cancer are not eligible; staging to rule out metastatic disease is recommended for clinical stage III patients
- •Patients with multicentric or bilateral disease are eligible if the target lesion meets eligibility criteria
- •Patient agrees to undergo pretreatment research biopsies
- •No prior chemotherapy, hormone therapy, or radiation therapy with therapeutic intent for this cancer
- •The target lesion in the breast must be >= 1 cm, clinically or radiographically; palpable or radiographically measurable axillary adenopathy will be recorded but will not serve as measurable disease for the primary endpoint; patients with axillary disease only (no identifiable tumor in the breast that is >= 1 cm on physical exam or radiographic study) are not eligible to participate
- •Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower gastrointestinal [GI] bleeding) within 6 months of registration are not eligible
- •No serious or non-healing wound, skin ulcers or bone fracture; no abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within the past 6 months; no major surgical procedure within 28 days prior to randomization or anticipation of need for major surgery during the course of study
- •The following are not considered to be major surgical procedures that would be prohibited in the 28 days prior to, or following study randomization: obtaining the required research needle biopsies; placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical resection; placement of a port for central venous access; fine needle aspiration of a prominent or suspicious axillary lymph node; needle biopsy of a clinically or radiographically detected lesion to rule out metastatic disease; or pretreatment sentinel lymph node sampling
- •No baseline neuropathy grade >= 2
- •Zubrod performance status 0-1
- •Pregnant or nursing women are not eligible; all women of reproductive potential must have a negative pregnancy test at baseline and agree to use an effective, non-hormonal method of contraception during the entire period of treatment on the study
- •Patients with congestive heart failure are not eligible, nor are patients with myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack (TIA) within the past 12 months, uncontrolled hypertension (systolic blood pressure [SBP] > 160 or diastolic blood pressure [DBP] > 90), uncontrolled or symptomatic arrhythmia, or grade II or greater peripheral vascular disease
- •Patients must have a pretreatment multi gated acquisition (MUGA) scan or echocardiogram with a left ventricular ejection fraction (LVEF) above the institutional lower limit of normal
- •Granulocytes > 1,000/mcl
- •Platelets > 100,000/mcl
- •Total bilirubin =< 1.5 x upper limits of normal
- •Calculated or measured > 30 ml/min
- •Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1
- •Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr, or UPC ratio < 1 to allow participation in the study
- •Serum alanine aminotransferase (ALT) =< 2.5 x upper limits of normal
- •Serum beta human chorionic gonadotropin (HCG) negative (for women of child bearing potential)
- •Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x upper limit of normal (ULN)
- •Unless patient is on therapeutic doses of warfarin; if so, the patient must have an INR =< 3 on a stable dose of warfarin, must have not active bleeding or pathologic condition that is associated with a high risk of bleeding
排除标准
- 未提供
研究组 & 干预措施
Arm III (paclitaxel, ddAC, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (paclitaxel, ddAC, bevacizumab)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
干预措施: Cyclophosphamide (Drug)
Arm II (paclitaxel, ddAC, bevacizumab)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm II (paclitaxel, ddAC, bevacizumab)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (paclitaxel, ddAC, bevacizumab)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
干预措施: Paclitaxel (Drug)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (paclitaxel, doxorubicin, cyclophosphamide)
Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19.
干预措施: Laboratory Biomarker Analysis (Other)
Arm III (paclitaxel, ddAC, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
干预措施: Cyclophosphamide (Drug)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Cyclophosphamide (Drug)
Arm II (paclitaxel, ddAC, bevacizumab)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes in weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17.
干预措施: Bevacizumab (Biological)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Carboplatin (Drug)
Arm III (paclitaxel, ddAC, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm I (paclitaxel, doxorubicin, cyclophosphamide)
Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19.
干预措施: Cyclophosphamide (Drug)
Arm III (paclitaxel, ddAC, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
干预措施: Paclitaxel (Drug)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Paclitaxel (Drug)
Arm I (paclitaxel, doxorubicin, cyclophosphamide)
Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm IV (paclitaxel, ddAC, bevacizumab, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I, bevacizumab as in Arm II, and carboplatin as in Arm III.
干预措施: Bevacizumab (Biological)
Arm I (paclitaxel, doxorubicin, cyclophosphamide)
Patients receive paclitaxel IV over 60 minutes once weekly in weeks 1-12. Patients then receive dose-dense doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 5-30 minutes (ddAC) once in weeks 13, 15, 17, and 19.
干预措施: Paclitaxel (Drug)
Arm III (paclitaxel, ddAC, carboplatin)
Patients receive paclitaxel and ddAC as in Arm I. Patients also receive carboplatin IV over 30 minutes once in weeks 1, 4, 7, and 10.
干预措施: Carboplatin (Drug)
结局指标
主要结局
Pathologic Complete Response (pCR) in the Breast. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is).
时间窗: At the time of definitive surgical removal, up to 28 weeks
Assessment of the difference in percentage of participants with pCR in the breast between regimens that contain carboplatin (arms 3\&4) versus not (arms 1\&2) will use a one-sided chi square test. 95% confidence intervals around the incidence of pCR will also be constructed using exact binomial methods.
次要结局
- Overall Survival(up to 10 years)
- Pathologic Stage in the Breast and in the Breast Plus Axilla as Measured by American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Staging Criteria (Version 6)(at definitive surgery, up to 28 weeks)
- Radiographic Response Assessed by Tumor Measurement(Baseline; at completion of neoadjuvant therapy)
- Clinical Response Assessed by Tumor Measurement(Baseline; at completion of neoadjuvant therapy)
- Recurrence-free Survival(up to 10 years)
- Count of Participants With a First Failure, Defined as First Instance of Ipsilateral Invasive Breast Tumor Recurrence, Local/Regional Invasive Breast Cancer Recurrence, Distant Recurrence, or Death From Any Cause(up to 10 years)
- Incidence and Severity of Post-op Complications, Namely Excessive Bleeding, Delayed Wound Healing, and Wound Dehiscence.(at definitive surgery, up to 28 weeks)
- Pathologic Complete Response (pCR) in the Breast and Axilla. Defined as the Absence of Residual Invasive Carcinoma in the Breast (ypT0/is) Plus the Absence of Any Tumor Deposit >0.2 mm in Sampled Axillary Nodes (ypT0/isN0).(At the time of definitive surgical removal, up to 28 weeks)