I. Compare the disease-free survival (DFS) of patients with lymph node-positive or high-risk, lymph node-negative breast cancer treated with adjuvant therapy comprising doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with vs. without bevacizumab.
I. Compare the overall survival of patients treated with these regimens. II. Determine the toxicity of these regimens. III. Compare the efficacy of short-term (20-24 weeks) vs long-term (50-54 weeks) bevacizumab, in terms of DFS, in these patients.
IV. Evaluate the association between outcomes (disease-free survival, overall survival and toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome wide evaluations).
V. Compare quality of life patients treated with these regimens, in terms of physical symptoms, physical functioning, psychological state and social functioning over an 18 month period. (QOL closed as of 05/28/10) VI. Determine the impact of theoretical biomarker information on patients' willingness to accept the toxicities of bevacizumab for the estimated potential benefit.
VII. 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 DNA) and host factors (e.g., estrogen, insulin-IGF axis, inflammation, etc).
VIII. Create a biorepository of metastatic tumor samples in patients who have had a late relapse.
XV. Determine body mass index (BMI) and comorbidity burden in patients with operable breast cancer five or more years after diagnosis.
X. 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: This is a randomized, partially double-blind, placebo-controlled, partially open-label, multicenter study. Patients are stratified according to planned dose schedule of doxorubicin hydrochloride and cyclophosphamide (every 3 weeks vs every 2 weeks). Patients are further stratified according to estrogen receptor status (positive vs negative), lymph node involvement (node-negative vs 1-3 positive node[s] vs ≥ 4 positive nodes), and received/planned treatment (lumpectomy and whole breast radiation therapy vs lumpectomy and accelerated partial-breast radiation therapy [before or after chemotherapy] vs mastectomy without radiation therapy vs mastectomy [with local or regional]). Patients are randomized to 1 of 3 treatment arms (20% of patients are randomized to Arm I, 40% to Arm II, and 40% to Arm III).
ARM I: 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.
ARM II: 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.
ARM III: 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 open-label bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.
In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients complete quality of life (QOL) questionnaires followed by telephone QOL interviews at baseline and periodically. (QOL closed as of 05/28/10)
After completion of study treatment, patients are followed periodically for up to 15 years.
- Histologically confirmed adenocarcinoma of the breast at significant risk of distant recurrence based on at least one of the following criteria:
- 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
- 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)
- 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
- Planned post-lumpectomy radiation therapy required, including any of the following:
- Whole breast radiation therapy after chemotherapy
- Accelerated partial breast radiation therapy after chemotherapy
- Accelerated partial breast radiation therapy prior to chemotherapy
- 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
- Absolute neutrophil count >= 1,000/mm^3
- Platelet count >= 100,000/mm^3
- Bilirubin =< 1.5 mg/dL
- Aspartate transferase (AST) =< 2 times upper limit of normal(ULN)
- Creatinine =< 1.5 mg/dL
- Urine protein:creatinine ratio < 1.0 or 24-hour protein
- Partial thromboplastin time (PTT) =< 1.5 times ULN
- Left ventricle ejection fraction (LVEF) normal by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
- 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
- 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 hybridisation [FISH] ratio >= 2) breast cancer are not eligible
- Patients with synchronous bilateral breast cancer (diagnosed =< 1 month) if the higher 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
- Patients must not have had any major surgical procedure within 28 days of planned treatment start date
- 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
- 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)
- Patients must not have a bleeding diathesis, hereditary or acquired bleeding disorder or coagulopathy
- Patients must not have a non-healing wound or fracture; patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization are not eligible
- Patients must not have hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
- Women must not be pregnant or breast-feeding due to the potential harmful effects of bevacizumab on the developing fetus; all females of childbearing potential must have a blood or urine test within 7 days prior to randomization to rule out pregnancy
- Women of childbearing potential and sexually active males must use an accepted and effective method of contraception
Last updated: 04/09/2013
NCT ID: NCT00433511