Bevacizumab and Combination Chemotherapy in Patients With Lymph Node Positive Breast Cancer

• Proportion of Patients With Absolute Decrease in Left Ventricular Ejection Fraction (LVEF) Levels Post Doxorubicin and Cyclophosphamide(AC) [ Time Frame: assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment ] [ Designated as safety issue: Yes ]
  The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post doxorubicin and cyclophosphamide (AC) Day 1 Cycle 5 (DIC5). 207 patients who were treated and had baseline and DIC5 LVEF values were included in the analysis.
• Proportion of Patients With Absolute Decrease in LVEF Levels Post Bevacizumab [ Time Frame: assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment ] [ Designated as safety issue: Yes ]
  The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post bevacizumab (the end of treatment). 158 patients who were treated and had baseline and end of treatment LVEF values were included in the analysis.

This phase II trial is studying how well giving bevacizumab together with combination chemotherapy works in treating patients who have undergone surgery for breast cancer that has spread to the lymph nodes. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with more than one chemotherapy drug (combination chemotherapy), may be a better way to block tumor growth.

PRIMARY OBJECTIVES:

I. Determine the incidence of clinically apparent cardiac dysfunction in patients with resected lymph node-positive breast cancer treated with adjuvant bevacizumab and dose dense doxorubicin and cyclophosphamide followed by paclitaxel.

SECONDARY OBJECTIVES:

I. Determine the changes in left ventricular ejection fraction (LVEF) in patients treated with this regimen.

II. Determine the non-cardiac toxicity of this regimen in these patients.

OUTLINE: This is a non-randomized, multicenter study. Patients are sequentially assigned to 1 of 2 treatment arms.

ARM A: Patients receive doxorubicin IV, cyclophosphamide IV over 20-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SQ) on days 2-11 or pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients then receive paclitaxel IV over 3 hours and bevacizumab IV over 30-90 minutes on day 1. Patients also receive G-CSF or pegfilgrastim as above. Treatment with paclitaxel, bevacizumab, and G-CSF or pegfilgrastim repeats every 14 days for 4 courses. Patients then receive bevacizumab alone every 14 days for up to 18 courses.

ARM B: Patients receive doxorubicin, cyclophosphamide, and G-CSF or pegfilgrastim as in group I. Patients then receive paclitaxel, bevacizumab, and G-CSF or pegfilgrastim as in group I. Patients then receive bevacizumab alone every 14 days for up to 22 courses.

Treatment in both groups continues in the absence of disease recurrence or unacceptable toxicity.

Patients who require radiotherapy (post-lumpectomy) or who plan radiotherapy at the discretion of the investigator (post-mastectomy) undergo radiotherapy beginning within 6 weeks after the completion of chemotherapy.

Premenopausal patients with estrogen receptor (ER) and / or progesterone receptor (PR) positive disease receive oral tamoxifen once daily for 5 years beginning at the time of radiotherapy or within 6 weeks after the completion of chemotherapy. Postmenopausal patients with ER and / or PR positive disease receive an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen followed by an aromatase inhibitor once daily for up to 10 years.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years from study entry.

• Biological: bevacizumab
  10 mg/kg intravenous (IV) infusion after doxorubicin and cyclophosphamide (AC) on day 1 of each cycle (14 days) for 26 cycles for both Arms. Bevacizumab binds Vascular Endothelial Growth Factor (VEGF) preventing the binding of VEGF to its receptors (flt-1 and kdr), thus inhibiting endothelial cell proliferation and new blood vessel formation.
  Other Names:

  • NSC 704865
  • RhuMAb VEGF
  • Recombinant Humanized Monoclonal Anti-VEGF Antibody
• Biological: filgrastim
  Filgrastim (5μg/kg subcutaneously (SQ) ) days 2-11 or Pegfilgrastim (6 mg SQ) day 2 of each cycle (14 days). Filgrastim or Pegfilgrastim are not required during bevacizumab monotherapy.Filgrastim is a human granulocyte colony-stimulating factor (G-CSF).
  Other Name: Neopogen
• Biological: pegfilgrastim
  Filgrastim (5μg/kg SQ) days 2-11 or Pegfilgrastim (6 mg SQ) day 2 of each cycle (14 days). Filgrastim or Pegfilgrastim are not required during bevacizumab monotherapy.Filgrastim is a human granulocyte colony-stimulating factor (G-CSF).
  Other Names:

  • Neulasta
  • G-CSF
  • granlocyte - colony stimulating factor
• Drug: cyclophosphamide
  600 mg/m2, IV infusion in 250 ml saline solution (NS) over 20-30 minutes on day 1 of each cycle (14 days) for 4 cycles.
  Other Names:

  • Cytoxan
  • Neosar
  • CTX
  • CPM
• Drug: doxorubicin hydrochloride
  60 mg/m2, IV push through running IV of NS, day 1 of each cycle (14 days) for 4 cycles
  Other Names:

  • Adriamycin
  • Rubex
  • Adriamycin RDF
  • Adriamycin PFS
  • hydroxydaunorubicin
  • hydroxydaunomycin
  • ADR
• Drug: paclitaxel
  175 mg/m2 IV infusion in 250 ml NS or D5W over 3 hours on day 1 of each cycle for 4 cycles
  Other Names:

  • Taxol
  • NSC 673089

• Experimental: Arm A (ddBAC > BT > B)
  Interventions:

  • Biological: bevacizumab
  • Biological: filgrastim
  • Biological: pegfilgrastim
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: paclitaxel
• Active Comparator: Arm B (ddAC > BT > B)
  Interventions:

  • Biological: bevacizumab
  • Biological: filgrastim
  • Biological: pegfilgrastim
  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: paclitaxel

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the breast
• Node-positive disease in 1 or more axillary or internal mammary lymph node by histology with hematoxylin and eosin staining

• Has undergone prior definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, lumpectomy and axillary dissection or lumpectomy and sentinel node biopsy within the past 29-84 days (arm A only)

  • Surgical margins must be histologically free of invasive tumor and ductal carcinoma in situ, but lobular carcinoma in situ allowed
• Synchronous bilateral breast cancer diagnosed within the past month allowed provided the higher TNM (Tumor,Node,Metastasis) stage tumor meets study eligibility criteria
• Age>=18
• ECOG performance status of 0-2

• Adequate organ function as evidenced by following, obtained within 8 weeks prior to registration:

  • Absolute neutrophil count ≥ 1,000/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Bilirubin ≤ 1.5 mg/dL
  • Aspartate aminotransferase (AST) ≤ 2 times upper limit normal (ULN)
  • Prothrombin time international normalized ratio (PT INR) ≤ 1.5 times normal
  • Partial thromboplastin time (PTT) ≤ 1.5 times normal
  • Creatinine ≤ 1.5 mg/dL
  • Urine protein:creatinine ratio < 1.0
  • Left ventricular ejection fraction (LVEF) normal by multi gated acquisition scan (MUGA) or echocardiogram (ECHO)
• Fertile patients must use effective contraception during and for 3-4 months after completion of study treatment
• Prior tamoxifen or raloxifene for chemoprevention allowed

• More than 4 weeks since prior major surgery

  • Non-operative biopsy or placement of a vascular access device is not considered major surgery
• Regular use of cyclo-oxygenase-2 inhibitors or low-dose aspirin allowed

Exclusion Criteria:

• With immunohistologic staining as the only evidence of nodal involvement
• Her2/neu-positive disease(i.e.,3+ by immunohistochemistry or positive by fluorescent in situ hybridization)
• Clinical evidence of inflammatory disease or fixed axillary nodes (N2)
• History of myocardial infarction within the past year
• History of unstable angina within the past year
• History of arterial thrombotic events within the past year
• Uncontrolled or clinically significant arrhythmia
• New York Heart Association grade II-IV congestive heart failure
• Peripheral vascular disease ≥ grade II
• Uncontrolled hypertension, defined as systolic blood pressure (BP)>160 mm Hg or diastolic BP>90 mm Hg
• History of deep venous thrombosis
• History of cerebrovascular disease, including transient ischemic attack or stroke
• Other clinically significant cardiovascular disease
• History of pulmonary embolism
• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• Non-healing wound or bone fracture
• Hypersensitivity to paclitaxel or drugs using Cremophor
• Hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• Pregnant
• Nursing during and for ≥ 3-4 months after completion of study treatment
• Prior cytotoxic chemotherapy for breast cancer
• Prior anthracycline, anthracenedione, or taxane for any condition
• Prior hormonal therapy for breast cancer
• Other concurrent tamoxifen or raloxifene
• Prior radiotherapy for breast cancer
• Concurrent radiotherapy to the internal mammary chain

• Concurrent therapeutic anticoagulants

  • Concurrent prophylactic use of anticoagulants to maintain patency of vascular assess device allowed
• Concurrent regular use of aspirin (i.e., daily for ≥ 10 days at doses of > 325 mg/day) or regular therapeutic doses of other nonsteroidal anti-inflammatory drugs known to inhibit platelet function

• Other concurrent drugs known to inhibit platelet function, including any of the following:

  • Dipyridamole
  • Ticlopidine
  • Clopidogrel
  • Cilostazol
• Concurrent cardioprotectant agents

• North Central Cancer Treatment Group
• Cancer and Leukemia Group B