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Phase II Feasibility Trial Incorporating Bevacizumab Into Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Patients With Lymph Node Positive Breast Cancer

Phase 2
18 Years
Not Enrolling
Breast Cancer

Thank you

Trial Information

Phase II Feasibility Trial Incorporating Bevacizumab Into Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Patients With Lymph Node Positive Breast Cancer


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.


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

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.

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

- 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

- 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

- Dipyridamole

- Ticlopidine

- Clopidogrel

- Cilostazol

- Concurrent cardioprotectant agents

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Congestive Heart Failure Rate

Outcome Description:

Clinical congestive heart failure includes patients with symptomatic decline in LVEF to at or below the lower limit of normal (LLN), or symptomatic diastolic dysfunction. 223 treated patients were included in the analysis.

Outcome Time Frame:

assessed on day 1 of cycles 5, 9, 17 and 25, and at end of treatment, then every 3 months for <2 years and every 6 months for 2-3 years from study entry

Safety Issue:


Principal Investigator

Kathy Miller, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Indiana University Melvin and Bren Simon Cancer Center


United States: Federal Government

Study ID:




Start Date:

October 2005

Completion Date:

September 2009

Related Keywords:

  • Breast Cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • male breast cancer
  • lymph node positive breast cancer
  • Breast Neoplasms



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