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A Phase II Clinical Trial of Bevacizumab Beginning Concurrently With a Sequential Regimen of Doxorubicin and Cyclophosphamide Followed by Docetaxel and Capecitabine as Neoadjuvant Therapy Followed by Postoperative Bevacizumab Alone for Women With Locally Advanced Breast Cancer

Phase 2
18 Years
Not Enrolling
Breast Cancer

Thank you

Trial Information

A Phase II Clinical Trial of Bevacizumab Beginning Concurrently With a Sequential Regimen of Doxorubicin and Cyclophosphamide Followed by Docetaxel and Capecitabine as Neoadjuvant Therapy Followed by Postoperative Bevacizumab Alone for Women With Locally Advanced Breast Cancer

Initial trials of neoadjuvant chemotherapy administered for locally advanced tumors,
including those in breast cancer, demonstrated therapy could induce sufficient tumor
regression to allow for the resection of otherwise unresectable tumors. Subsequent
demonstration of the equivalence of lumpectomy to mastectomy in patients with operable
breast cancer, stimulated interest in the concept of using preoperative chemotherapy to
reduce large, but operable, primary tumors to allow for lumpectomy in women who would
otherwise require a mastectomy. Given the data from previous studies, it is appropriate to
continue development of sequential doxorubicin/cyclophosphamide/docetaxel regimens to
improve on clinical and pathologic response rates. FB-4 is a Phase II, single arm study for
women with locally advanced human epidermal growth factor receptor 2 (HER2)-negative breast
cancer diagnosed by core needle biopsy. The primary aim of the study is to determine the
pathologic complete response rate in the breast following neoadjuvant chemotherapy combined
with bevacizumab.

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

- 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

- 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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathologic Complete Response (pCR) in the Breast

Outcome Description:

Measured by no histologic evidence of invasive tumor cells in the surgical breast specimen

Outcome Time Frame:

Assessed at the time of surgery

Safety Issue:


Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.


United States: Food and Drug Administration

Study ID:




Start Date:

August 2006

Completion Date:

November 2009

Related Keywords:

  • Breast Cancer
  • Doxorubicin
  • Cyclophosphamide
  • Bevacizumab
  • Capecitabine
  • Docetaxel
  • Breast cancer
  • Locally advanced
  • Neoadjuvant
  • Locally advanced breast cancer
  • Breast Neoplasms



NSABP Foundation, Inc. Pittsburgh, Pennsylvania  15212