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
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 breast 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.
I. To determine the disease-free survival (defined as invasive disease-free survival [IFDS]) of patients 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.
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).
QUALITY OF LIFE OBJECTIVES:
I. To compare the quality of life of breast cancer patients treated with AC/paclitaxel and bevacizumab or placebo, in terms of physical symptoms, physical functioning, psychological state and social functioning over an 18 month period.
II. To determine the impact of theoretical biomarker information on patients' willingness to accept the toxicities of bevacizumab for the estimated potential benefit.
DETERMINANTS OF LATE RELAPSE ANCILLARY STUDY (EL112LAB):
I. To create a biospecimen repository including plasma, serum and CellSearch cassettes containing circulating tumor cells (CTC) for evaluating determinants of late relapse, including candidate biomarkers reflecting occult tumor burden (e.g., CTCs and plasma tumor deoxyribonucleic acid [DNA]) and host factors (e.g., estrogen, insulin-insulin-like growth factor [IGF] axis, inflammation, etc).
II. To create a biorepository of metastatic tumor samples in patients who have had a late relapse.
III. To determine body mass index (BMI) and comorbidity burden in patients with operable breast cancer five or more years after diagnosis.
IV. To determine whether there is a relationship between late relapse and BMI at diagnosis and at 5 years after diagnosis, and whether BMI-associated inflammatory and/or metabolic biomarkers are associated with early and late recurrence.
OUTLINE: Patients are randomized in a 1:2:2 fashion to Arms A, B or C.
ARM A: Patients receive doxorubicin hydrochloride intravenously (IV) at 60 mg/m2, cyclophosphamide IV at 600 mg/m2 over 20-30 minutes, and placebo IV at 10 or 15 mg/kg 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 at 80 mg/m2 over 1 hour on days 1, 8, and 15 and placebo IV 15 mg/kg over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.
ARM B: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm A and bevacizumab IV at 10 or 15 mg/kg 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 A and bevacizumab at 15 mg/kg IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.
ARM C: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm A and bevacizumab as in arm B. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm A and bevacizumab as in arm B. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Within the following 2 monthsr, patients then receive bevacizumab IV at 15 mg/kg over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses. The monotherapy of bevacizumab is considered as Arm D in this study.
In all arms, treatment continues in the absence of disease recurrence or unacceptable toxicity.
After completion of study treatment, patients are followed up for 15 years.
18 Years and up
Accepting Healthy Volunteers?
- 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
- Adequate organ function within <= 8 weeks prior to randomization, as measured by Absolute neutrophil count ≥ 1000/mm3, Platelet count ≥ 100,000/mm3, Total bilirubin ≤ 1.5 mg/dL, AST ≤ 2 X upper limit of normal, Serum creatinine ≤ 1.5 mg/dL, Urine protein: creatinine (UPC) ratio <1.0 or 24-hour protein, partial thromboplastin time (PTT) ≤ 1.5 X upper limit of normal (ULN) and left ventricular ejection fraction (LVEF) ≥ institutional limits of normal by multigated acquisition (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 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 who require full-dose anticoagulation may enroll provided they meet the following criteria:
- The patient must have an in-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of warfarin or be on stable dose of low molecular weight (LMW) heparin
- The patient must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. varices)
- NOTE: prophylactic use of anticoagulants to maintain patency of a vascular access device is permitted
- Women of childbearing potential and sexually active males must use an accepted and effective method of contraception
- Patients with human epidermal growth factor receptor (HER)2 + (3+ by immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] ratio >= 2) breast cancer
- Clinical evidence of inflammatory disease or fixed axillary nodes at diagnosis
- Prior cytotoxic chemotherapy or hormonal therapy for this breast cancer
- Prior treatment with an anthracycline, anthracenedione or taxane for any condition
- 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
- 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
- Placement of a vascular access device within 24 hours of planned day 1 of treatment
- 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
- Active at study entry
- 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
- Bleeding diathesis, hereditary or acquired bleeding disorder or coagulopathy
- Non-healing wound or fracture
- Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
- Hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
- Being pregnant or breast-feeding; all females of childbearing potential must have a blood or urine test within 7 days prior to randomization to rule out pregnancy