Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer
Condition: Breast Adenocarcinoma
MeSH terms: Adenocarcinoma
Intervention: Bevacizumab; Cyclophosphamide; Doxorubicin Hydrochloride; Laboratory Biomarker Analysis; Paclitaxel; Placebo Administration; Quality-of-Life Assessment
Intervention description: Given IV; Given IV; Given IV; Correlative studies; Given IV; Given IV; Ancillary studies (closed as of 5/28/10)
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Bevacizumab; Doxorubicin; Liposomal doxorubicin; Albumin-Bound Paclitaxel; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4994.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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:

               -  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

          -  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; 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