A Clinical Trial Comparing the Combination of TC Plus Bevacizumab to TC Alone and to TAC for Women With Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer

Not Recruiting

Trial ID: NCT00887536


The main purpose of this study is to learn if adding bevacizumab to standard treatment with chemotherapy (docetaxel, doxorubicin, and cyclophosphamide) for early stage HER2-negative breast cancer will prevent breast cancer from returning. A second purpose of this study is to learn if adding bevacizumab to treatment with chemotherapy will help women with HER2-negative breast cancer live longer. The researchers also want to learn about the side effects of the combination of drugs used in this study.

Official Title

A Phase III Clinical Trial Comparing the Combination of TC Plus Bevacizumab to TC Alone and to TAC for Women With Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer

Stanford Investigator(s)

Irene Wapnir, MD
Irene Wapnir, MD

Professor of Surgery (General Surgery)


Inclusion Criteria:

   - Patients must be female.

   - The patient must be greater than or equal to 18 years of age and less than or equal to
   70 years of age.

   - The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
   of 0 or 1.

   - The tumor must be unilateral invasive adenocarcinoma of the breast on histologic

   - The breast cancer must be HER2-negative based on current American Society of Clinical
   Oncology (ASCO)/College of American Pathologists (CAP) Guideline Recommendations for
   Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. If the result of
   the in situ hybridization testing (FISH, chromagen in situ hybridization (CISH), or
   other) is equivocal, the patient is eligible if there is no plan to administer
   HER2-targeted therapy.

   - All of the following staging criteria (according to the 6th edition of the American
   Joint Committee on Cancer (AJCC) Cancer Staging Manual) must be met: By pathologic
   evaluation, primary tumor must be pT1-3; By pathologic evaluation, ipsilateral nodes
   must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b. If pN0, at least one
   of the following criteria must be met: ER negative and PgR negative; or Pathologic
   tumor size greater than 2.0 cm; or T1c (pathologic tumor size greater than 1.0 cm but
   less than or equal to 2.0 cm) and ER positive (PgR status may be positive or negative)
   and either Oncotype DX® Recurrence Score of greater than or equal to 25 or grade 3

   - Patients must have undergone either a total mastectomy or breast-conserving surgery

   - For patients who undergo lumpectomy, the margins of the resected specimen must be
   histologically free of invasive tumor and DCIS as determined by the local pathologist.
   If pathologic examination demonstrates tumor at the line of resection, additional
   operative procedures must be performed to obtain clear margins. If tumor is still
   present at the resected margin after re-excision(s), the patient must undergo total
   mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in
   situ [LCIS] are eligible without additional resection.)

   - For patients who undergo mastectomy, margins must be histologically free of invasive
   tumor and DCIS.

   - Patients must have completed one of the following procedures for evaluation of
   pathologic nodal status: Sentinel lymphadenectomy alone if pathologic nodal staging
   based on sentinel lymphadenectomy is pN0, pN1mi, or pN1b; Sentinel lymphadenectomy
   followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN)
   is positive; or Axillary lymphadenectomy without SN isolation procedure.

   - The interval between the last surgery for breast cancer (treatment or staging) and
   randomization must be at least 28 days but no more than 84 days.

   - Patients must have ER analysis performed on the primary tumor prior to randomization.
   If ER analysis is negative, then PgR analysis must also be performed. (Either a core
   biopsy or surgical resection specimen can be used for ER/PgR testing.)

   - The most recent postoperative blood counts must meet the following criteria: Absolute
   neutrophil count (ANC) must be greater than or equal to 1200/mm3; platelet count must
   be greater than or equal to 100,000/mm3; and hemoglobin must be greater than or equal
   to 10 g/dL.

   - The following criteria for evidence of adequate hepatic function must be met based on
   the results of the most recent postoperative tests: total bilirubin must be less than
   or equal to upper limits of normal (ULN)for the lab unless the patient has a bilirubin
   elevation less 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 or
   equal to 2.5 x ULN for the lab; and AST must be less than or equal to 1.5 x ULN for
   the lab. Alkaline phosphatase and aspartate transaminase (AST) may not both be greater
   than the ULN. For example, if the alkaline phosphatase is greater than the ULN but
   less than or equal to 2.5 x ULN, then the AST must be less than or equal to the ULN.
   If the AST is greater than the ULN but less than or equal to 1.5 x ULN, then the
   alkaline phosphatase must be less than or equal to ULN.

   - Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion
   in the study if liver imaging (CT, MRI, PET-CT, or PET scan) does not demonstrate
   metastatic disease and the requirements for adequate hepatic function are met.

   - Patients with alkaline phosphatase that is greater than ULN but less than or equal to
   2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT, or PET scan
   does not demonstrate metastatic disease.

   - The most recent postoperative serum creatinine must be less than or equal to ULN for
   the lab.

   - A urine sample must be tested for proteinuria by the dipstick method. Eligibility must
   be based on the most recent postoperative test result(s) performed within 6 weeks
   prior to randomization. Urine dipstick must indicate 0-1+ protein. If dipstick reading
   is greater than or equal to 2+, a 24-hour urine specimen must be collected and must
   demonstrate less than 1 gram of protein.

   - Left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or
   multigated acquisition (MUGA) scan must be performed within 90 days prior to
   randomization. The LVEF must be greater than or equal to 50% regardless of the
   facility's lower limits of normal (LLN).

Exclusion Criteria:

   - T4 tumors including inflammatory breast cancer.

   - Definitive clinical or radiologic evidence of metastatic disease.

   - Synchronous or metachronous contralateral invasive breast cancer. (Patients with
   synchronous and/or metachronous contralateral DCIS are eligible.)

   - Any history of ipsilateral invasive breast cancer or ipsilateral DCIS.

   - History of non-breast malignancies within 5 years prior to randomization, except for
   the following: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma
   in situ, and basal cell and squamous cell carcinomas of the skin.

   - Previous therapy with anthracyclines, taxanes, or bevacizumab for any malignancy.

   - Chemotherapy administered for the currently diagnosed breast cancer prior to

   - Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other
   SERM) or an aromatase inhibitor. (Patients are eligible if these medications are
   discontinued prior to randomization.)

   - Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
   therapy. Patients are eligible if these medications are discontinued prior to

   - Active hepatitis B or hepatitis C with abnormal liver function tests.

   - Cardiac disease (history of and/or active disease) that would preclude the use of the
   drugs included in the treatment regimens. This includes but is not confined to 1)
   Active cardiac disease: angina pectoris that requires the use of anti-anginal
   medication; ventricular arrhythmias except for benign premature ventricular
   contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not
   controlled with medication; conduction abnormality requiring a pacemaker; valvular
   disease with documented compromise in cardiac function; and symptomatic pericarditis,
   2) History of cardiac disease: myocardial infarction documented by elevated cardiac
   enzymes or persistent regional wall abnormalities on assessment of left ventricular
   (LV) function; history of documented congestive heart failure (CHF); and documented

   - Uncontrolled hypertension defined as systolic BP greater than 150 mmHg or diastolic BP
   greater than 90 mmHg, with or without anti-hypertensive medication. Patients with
   initial BP elevations are eligible if initiation or adjustment of BP medication lowers
   pressure to meet entry criteria.

   - History of hypertensive crisis or hypertensive encephalopathy.

   - History of transient ischemic attack (TIA) or cerebrovascular accident (CVA).

   - History of any arterial thrombotic event within 12 months prior to randomization.

   - Symptomatic peripheral vascular disease.

   - Intrinsic lung disease resulting in dyspnea.

   - Unstable diabetes mellitus.

   - Active infection or chronic infection requiring suppressive antibiotics.

   - History of a major organ allograft or condition requiring chronic immunosuppression,
   e.g., kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases.
   (Patients who have received corneal transplants, cadaver skin, or bone transplants are

   - Any significant bleeding within 180 days prior to randomization, exclusive of
   menorrhagia in premenopausal women.

   - Non-healing wound, skin ulcers, or incompletely healed bone fracture.

   - Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
   prior to the planned start of study therapy.

   - Anticipation of need for major surgical procedures during study therapy and for at
   least 3 months following completion of bevacizumab.

   - Gastroduodenal ulcer(s) documented by endoscopy to be active within 6 months before

   - History of GI perforation, abdominal fistulae, or intra-abdominal abscess.

   - Known bleeding diathesis or coagulopathy.

   - Requirement for therapeutic doses of coumadin or equivalent.

   - Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI
   Common Terminology Criteria for Adverse Events (CTCAE) v3.0.

   - Conditions that would prohibit administration of corticosteroids.

   - Chronic daily treatment with corticosteroids (dose of greater than or equal to 10
   mg/day methylprednisolone equivalent) (excluding inhaled steroids).

   - History of hypersensitivity reaction to drugs formulated with polysorbate 80.

   - Pregnancy or lactation at the time of study entry.

   - Other non-malignant systemic disease that would preclude the patient from receiving
   study treatment or would prevent required follow-up.

   - Psychiatric or addictive disorders or other conditions that, in the opinion of the
   investigator, would preclude the patient from meeting the study requirements.

   - Use of any investigational product within 4 weeks prior to randomization.


drug: bevacizumab

drug: docetaxel

drug: doxorubicin

drug: cyclophosphamide

drug: pegfilgrastim

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Cancer Clinical Trials Office

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