Therapy With Bevacizumab (BEV), Doxorubicin, and Cyclophosphamide Followed by BEV, Docetaxel, and Capecitabine Before Surgery Followed by BEV Alone After Surgery for Women With Locally Advanced Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Bevacizumab; Doxorubicin; Cyclophosphamide; Capecitabine; Docetaxel
Intervention description: 15 mg/kg IV every 21 days x 4 cycles, then after clinical response assessment, 15 mg/kg IV every 21 days x 2 cycles, then following surgery, 15 mg/kg every 21 days x 10 cycles; 60 mg/m^2 IV every 21 days x 4 cycles; 600 mg/m^2 IV every 21 days x 4 cycles; Following clinical response assessment, 650 mg/m^2 twice a day (orally), days 1-14 every 21 days x 4 cycles; Following clinical response assessment, 75 mg/m^2 IV every 21 days x 4 cycles
Intervention MeSH terms: Cyclophosphamide; Bevacizumab; Docetaxel; Doxorubicin; Capecitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NSABP; Doxorubicin; Cyclophosphamide; Bevacizumab; Capecitabine; Docetaxel; Breast cancer; Locally advanced; Neoadjuvant; Locally advanced breast cancer

Summary:

      Bevacizumab is an angiogenesis inhibitor which means it works to stop blood vessel formation
      in tumors. Without new blood vessels, the growth of a tumor is slowed. Chemotherapy drugs
      kill cancer cells more directly. This study will evaluate:

        -  How bevacizumab, given with chemotherapy before surgery, and then bevacizumab given
           alone after surgery, will affect locally advanced breast tumors

        -  Side effects from adding bevacizumab to chemotherapy

        -  Whether adding bevacizumab to chemotherapy for breast cancer will affect the heart

        -  If receiving bevacizumab will have any effect on how patients recover from surgery

        -  Side effects of the combinations of drugs used in this study
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must be female.

          -  The patient must be greater than/equal to 18 years old

          -  The diagnosis of invasive adenocarcinoma of the breast must have been made by core
             needle biopsy or limited incisional biopsy.

          -  Patients must have clinical Stage IIIA, IIIB, or IIIC disease (American Joint
             Committee on Cancer [AJCC] staging criteria) with a primary breast tumor that is
             greater than/equal to 2.0 cm measured by clinical exam, unless the patient has
             inflammatory breast carcinoma, in which case measurable disease is not required.

          -  Patients must have the ability to swallow oral medication.

          -  The patient's Eastern Cooperative Oncology Group (ECOG) performance status must be 0
             or 1.

          -  At the time of study entry, blood counts must meet the following criteria:

               -  Absolute neutrophil count (ANC) must be greater than/equal to 1200/mm3.

               -  Platelet count must be greater than/equal to 100,000/mm^3.

               -  Hemoglobin must be greater than/equal to 10 g/dL.

          -  The following criteria for evidence of adequate hepatic function must be met:

               -  total bilirubin must be less than/equal to upper limit of normal (ULN) for the
                  lab unless the patient has a grade 1 bilirubin elevation (greater than ULN to 1.5
                  x ULN) due to Gilbert's disease or similar syndrome involving slow conjugation of
                  bilirubin; and

               -  alkaline phosphatase must be less than 2.5 x ULN for the lab; and

               -  aspartate aminotransferase (AST) must be less than/equal to 1.5 x ULN for the
                  lab.

               -  Alkaline phosphatase and AST may not both be greater than the ULN. For example,
                  if the alkaline phosphatase is greater than the ULN but less than/equal to 2.5 x
                  ULN, then the AST must be less than/equal to the ULN. If the AST is greater than
                  the ULN but less than/equal to 1.5 x ULN, then the alkaline phosphatase must be
                  less than/equal to ULN.

          -  Patients with either skeletal pain or alkaline phosphatase that is greater than ULN
             but less than/equal to 2.5 x ULN are eligible for inclusion in the study if a bone
             scan or positron emission tomography (PET) scan does not demonstrate metastatic
             disease. Patients with suspicious findings on bone scan or PET scan are eligible if
             suspicious findings are confirmed as benign by x-ray, magnetic resonance imaging
             (MRI), or biopsy.

          -  Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion
             in the study if liver imaging (computed tomography [CT], MRI, or PET scan) does not
             demonstrate metastatic disease and adequate hepatic function.

          -  The following criteria for evidence of adequate renal function must be met:

               -  Serum creatinine less than/equal to ULN for the lab.

               -  Calculated creatinine clearance must be greater than 50 mL/min.

          -  Urine protein/creatinine (UPC) ratio must be less than 1.0.

          -  Patients must have their left ventricular ejection fraction (LVEF) assessed by
             multigated acquisition (MUGA) scan or echocardiogram within 3 months prior to study
             entry. The LVEF must be greater than/equal to the lower limit of normal (LLN) for the
             cardiac imaging facility performing the MUGA scan or echocardiogram. Note: If the
             cardiac imaging facility cannot provide a LLN, use 50% as the LLN value.

        Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF
        assessments to determine if bevacizumab therapy can be continued following doxorubicin and
        cyclophosphamide (AC) and postoperatively, it is critical that this baseline study be an
        accurate assessment of the patient's LVEF. If the baseline LVEF is greater than 65%, the
        MUGA scan or echocardiogram must be repeated prior to study entry. The lower of the two
        LVEF values should be used as the baseline LVEF.

          -  Patients must have an electrocardiogram (EKG) within 3 months prior to study entry.

        Exclusion Criteria:

          -  Tumor determined to be strongly HER2-positive by immunohistochemistry (3+) or by
             fluorescent in situ hybridization (positive for gene amplification).

          -  Excisional biopsy for this primary tumor.

          -  Synchronous bilateral invasive breast cancer.

          -  Surgical axillary staging procedure prior to study entry (Exceptions: 1) fine needle
             aspiration (FNA) of an axillary node is permitted for any patient, and 2) although not
             recommended, a sentinel lymph node biopsy for patients with clinically negative
             axillary nodes is permitted.)

          -  History of any of the following cancers:

               -  Ipsilateral breast cancer: invasive, ductal carcinoma in situ (DCIS) treated with
                  any therapy other than excision

               -  Contralateral breast cancer: invasive within the past 5 years (Patients with
                  history of DCIS or synchronous DCIS are eligible)

               -  History of non-breast malignancies within the 5 years prior to study entry.
                  Patients with the following cancers are eligible if diagnosed and treated within
                  the previous 5 years: carcinoma in situ of the cervix, carcinoma in situ of the
                  colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

          -  Prior therapy with anthracyclines, taxanes, capecitabine, or bevacizumab for any
             malignancy.

          -  Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal
             therapy administered for the currently diagnosed breast cancer prior to study entry.
             The only exception is hormonal therapy, which may have been given for up to a total of
             28 days anytime after diagnosis and before study entry. In such a case, hormonal
             therapy must stop at or before study entry and be re-started, if indicated, following
             chemotherapy.

          -  Any of the following cardiac conditions:

               -  angina pectoris that requires the use of anti-anginal medication;

               -  history of documented congestive heart failure;

               -  serious cardiac arrhythmia requiring medication;

               -  severe conduction abnormality;

               -  valvular disease with documented cardiac function compromise; or

               -  uncontrolled hypertension defined as blood pressure greater than 150/90 on
                  antihypertensive therapy. (Patients with hypertension that is well controlled on
                  medication are eligible.)

          -  History of myocardial infarction documented by elevated cardiac enzymes or persistent
             regional wall abnormalities on assessment of left ventricular (LV) function.

          -  History of transient ischemic attack (TIA) or cerebrovascular accident (CVA).

          -  History of other arterial thrombotic event within 12 months before study entry.

          -  Symptomatic peripheral vascular disease.

          -  Any significant bleeding within 6 months before study entry.

          -  Serious or non-healing wound, skin ulcers, or bone fracture.

          -  Gastroduodenal ulcer(s) determined by endoscopy to be active.

          -  Invasive procedures defined as follows:

               -  Major surgical procedure, open biopsy, or significant traumatic injury within 28
                  days prior to planned start of study therapy. (Note: Placement of a vascular
                  access device is not considered a major surgical procedure.)

               -  Anticipation of need for major surgical procedures (other than the required
                  breast surgery) during the course of the study.

          -  Known bleeding diathesis or coagulopathy. (Patients on warfarin with an in-range
             international normalized ratio [INR] [usually between 2 and 3] are eligible.)

          -  Other nonmalignant systemic disease (cardiovascular, renal, hepatic, diabetes, etc.)
             that would preclude the patient from receiving study treatment or would prevent
             required follow-up.

          -  Sensory/motor neuropathy greater than/equal to grade 2, as defined by the NCI's Common
             Terminology Criteria for Adverse Events Version 3.0 (CTCAE v3.0).

          -  Conditions that would prohibit administration of corticosteroids.

          -  History of hypersensitivity reaction to drugs formulated with polysorbate 80.

          -  Therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective
             estrogen receptor modulator (SERM), either for osteoporosis or breast cancer
             prevention. Patients are eligible only if these medications are discontinued prior to
             study entry.

          -  Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement
             therapy, etc. These patients are eligible if this therapy is discontinued prior to
             study entry. (Women of reproductive potential must agree to use an effective
             non-hormonal method of contraception during study therapy and for at least 3 months
             after completion of bevacizumab.)

          -  Pregnancy or lactation at the time of study entry.

          -  Use of any investigational agent within 4 weeks prior to enrollment in the study.

          -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
             investigator, would preclude the patient from meeting the study requirements.