Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy With or Without Bevacizumab in Treating Women With Stage I, Stage II, or Stage IIIA Breast Cancer That Can Be Removed By Surgery

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	NSABP-B-40 NCT00408408

Objectives

Primary

1. Compare the efficacy of docetaxel followed by doxorubicin hydrocloride and cyclophosphamide (AC) vs docetaxel and capecitabine followed by AC vs docetaxel and gemcitabine hydrochloride followed by AC, with or without bevacizumab, in terms of an increase in the rate of pathologic complete response (pCR) in the breast, in women with palpable or operable breast cancer.

Secondary

1. Compare docetaxel/capecitabine with AC vs docetaxel/gemcitabine hydrochloride with AC vs docetaxel with AC, with or without bevacizumab, in terms of the rate of pCR in the breast and all post-therapy lymph nodes evaluated histologically (pCR breast and nodes).
2. Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel and capecitabine with AC, and docetaxel and gemcitabine hydrochloride with AC) will increase the rate of pCR of the breast and nodes compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients.
3. Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical overall response (cOR) compared to docetaxel alone with or without bevacizumab in these patients.
4. Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens will increase the rate of cOR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients.
5. Determine whether the addition of capecitabine or gemcitabine hydrochloride to docetaxel, with or without bevacizumab, will increase the rate of clinical complete response (cCR) compared to docetaxel alone with or without bevacizumab in these patients.
6. Determine whether the addition of bevacizumab to the docetaxel/anthracycline-based regimens (docetaxel with AC, docetaxel/capecitabine with AC, and docetaxel/gemcitabine hydrochloride with AC) will increase the rate of cCR compared to the same docetaxel/anthracycline-based regimens without bevacizumab in these patients.
7. Identify gene expression profiles that can predict pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens with or without bevacizumab.
8. Identify gene expression profiles that can predict cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride with or without bevacizumab.
9. Determine the accuracy of an in vitro chemoresponse assay (ChemoFx®) as a predictor of pCR in patients treated with the different sequential docetaxel/anthracycline-based regimens without bevacizumab.
10. Determine the accuracy of ChemoFx® as a predictor of cOR in patients treated with docetaxel alone, docetaxel/capecitabine, or docetaxel/gemcitabine hydrochloride without bevacizumab in these patients.
11. Determine the impact of preoperative bevacizumab and sequential chemotherapy regimens and postoperative bevacizumab therapy on cardiac function in these patients.
12. Determine the impact of bevacizumab on surgical complications in these patients.
13. Determine the toxicity of the preoperative regimens and the toxicity of postoperative bevacizumab in these patients.
14. Compare the docetaxel/anthracycline-based regimens with vs without bevacizumab, in terms of an increase in disease-free survival, of these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed invasive adenocarcinoma of the breast
  • Primary breast tumor must be palpable and measure ≥ 2.0 cm on physical exam
  • No stage T4 disease
  • No ipsilateral cN2b or cN3 disease
    • cN1 or cN2a disease allowed
  • Histology confirmed by core-needle biopsy
• No prior surgical axillary staging procedure
  • Fine-needle aspiration or core biopsy of an axillary node allowed
  • Pre-neoadjuvant therapy sentinel lymph node biopsy allowed if axillary nodes clinically negative
• HER2-negative disease by immunohistochemistry (< 3+) or by fluorescent in situ hybridization (negative for gene amplification)
• No prior excisional or incisional biopsy for primary breast tumor
• No synchronous bilateral breast cancer (invasive or ductal carcinoma in situ [DCIS])
• No prior breast cancer, including DCIS
  • Prior lobular carcinoma in situ allowed
• No clinical or radiologic evidence of metastatic disease
• Hormone receptor status known

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior radiation therapy, chemotherapy, biologic therapy, and/or hormonal therapy for the currently diagnosed breast cancer
• No prior anthracyclines, taxanes, capecitabine, fluorouracil, gemcitabine hydrochloride, or bevacizumab for any malignancy
• No investigational agents within the past 30 days
• No major surgical procedure or open biopsy within the past 28 days
  • Placement of a vascular access device is not considered a major surgical procedure
• No concurrent sex hormone therapy (e.g., birth control pills, ovarian hormone replacement therapy)
• No concurrent hormonal agent, such as raloxifene, tamoxifen, or other selective estrogen-receptor modulator (SERM), either for osteoporosis or breast cancer prevention
• No major surgical procedures (other than the required breast surgery) during the course of the study
• No other concurrent anticancer therapy
• No concurrent partial breast radiation therapy and brachytherapy
• No concurrent participation in other clinical trials employing an investigational agent

Patient Characteristics:

• Female
• Menopausal status not specified
• ECOG performance status 0-1
• Not pregnant or nursing
• Negative pregnancy test
• LVEF ≥ the lower limit of normal or ≥ 50% by MUGA or echocardiogram within the past 3 months
• Absolute neutrophil count ≥ 1,200/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Alkaline phosphatase ≤ 2.5 times upper limit of normal (ULN)
• AST ≤ 1.5 times ULN
  • Alkaline phosphatase and AST must not both be > ULN
  • Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5 times ULN are allowed if bone scans do not demonstrate metastatic disease
  • AST or alkaline phosphatase > ULN allowed if liver imaging does not demonstrate metastatic disease
• Bilirubin normal (≤ 1.5 times ULN for Gilbert's disease or similar syndrome)
• Serum creatinine ≤ ULN
• Creatinine clearance > 50 mL/min
• Urine protein:urine creatinine ratio < 1.0
• Able to swallow oral medications
• No other malignancies except carcinoma in situ of the cervix or colon, melanoma in situ, or basal cell or squamous cell carcinoma of the skin, unless the patient is considered to be disease-free for the past 5 years and at low-risk for recurrence
• No cardiovascular-related condition that would preclude the use of anthracyclines, including any of the following:
  • Angina pectoris that requires the use of antianginal medication
  • History of documented congestive heart failure
  • Serious cardiac arrhythmia requiring medication
  • Severe conduction abnormality
  • Valvular disease with documented cardiac function compromise
  • Uncontrolled hypertension, defined as blood pressure > 150/90 mm Hg on antihypertensive therapy
    • Hypertension well controlled with medication allowed
• No history of myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular function
• No history of transient ischemic attack or cerebrovascular accident
• No arterial thrombotic event within the past 12 months
• No symptomatic peripheral vascular disease
• No significant nontraumatic bleeding within the past 6 months
• No significant traumatic injury within the past 28 days
• No serious or nonhealing wound, skin ulcers, or incompletely healed bone fracture
• No active (by endoscopy) gastroduodenal ulcer(s)
• No known bleeding diathesis or coagulopathy
  • Patients on warfarin with an in-range INR (between 2 and 3) allowed
• No sensory or motor neuropathy ≥ grade 2
• No conditions that would prohibit administration of corticosteroids
• No history of severe hypersensitivity reaction to drugs formulated with polysorbate 80
• No other nonmalignant systemic disease that would preclude study treatment or prevent required follow-up

Expected Enrollment

A total of 1,200 patients will be accrued for this study.

Outcomes

Pathologic complete response (pCR) of the primary tumor in the breast

pCR in the breast and nodes
Clinical overall response (cOR) following docetaxel alone, docetaxel/capecitabine, and docetaxel/gemcitabine hydrochloride, with or without bevacizumab, as assessed by physical exam at the completion of the docetaxel-based portion of chemotherapy
cOR as assessed by physical exam at the completion of the sequential chemotherapy regimens
Clinical complete response (cCR) following docetaxel alone, docetaxel/capecitabine, and docetaxel/gemcitabine hydrochloride, with or without bevacizumab, as assessed by physical exam at completion of therapy
cCR as assessed by physical exam at the completion of the sequential chemotherapy regimens
Percentage of cardiac events
Percentage of surgical complications
Toxicities
Disease-free survival
Incidence of recurrence after mastectomy
Incidence of local recurrence in the ipsilateral breast following lumpectomy
Incidence of regional recurrence
Incidence of distant recurrence
Incidence of contralateral breast cancer
Incidence of second primary cancer
Mortality from any cause prior to recurrence or second primary cancer

Outline

This is a randomized, multicenter study. Patients are stratified according to tumor size (2-4 cm vs > 4 cm), nodal status (negative vs positive), hormone receptor status (estrogen receptor [ER]-positive and/or progesterone-receptor [PgR]-positive vs ER- and PgR-negative), and age (< 50 years vs ≥ 50 years). Patients are randomized to 1 of 6 treatment arms.

• Arm I: Patients receive docetaxel IV over 60 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses. Patients then receive AC comprising doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses. Patients then undergo surgery (lumpectomy or mastectomy).
• Arm II: Patients receive bevacizumab IV over 30-90 minutes on day 1 and docetaxel as in Arm I. Treatment repeats every 3 weeks for up to 4 courses. Patients then receive AC as in Arm I and 2 additional courses of bevacizumab concurrent with the first 2 courses of AC. Patients then undergo surgery as in Arm I. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive docetaxel as in Arm I and oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for up to 4 courses. Patients then receive AC as in Arm I. Patients then undergo surgery as in Arm I.
• Arm IV: Patients receive bevacizumab as in Arm II and docetaxel and capecitabine as in Arm III. Treatment repeats every 3 weeks for up to 4 courses. Patients then receive bevacizumab IV over 30 minutes on day 1 and AC as in Arm I. Treatment repeats every 3 weeks for up to 4 courses (2 courses of bevacizumab). Patients then undergo surgery as in Arm I. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab as in Arm II.
• Arm V: Patients receive docetaxel as in Arm I and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 3 weeks for up to 4 courses. Patients then receive AC as in Arm I. Patients then undergo surgery as in Arm I.
• Arm VI: Patients receive docetaxel as in Arm I, gemcitabine hydrochloride as in Arm V, and bevacizumab as in Arm II. Patients then receive AC with bevacizumab as in Arm II. Patients then undergo surgery as in Arm I. At least 4-6 weeks after surgery, patients receive adjuvant bevacizumab as in Arm II.

Core needle biopsies are performed at baseline. Tumor tissue samples are also collected during definitive surgery. Samples are examined for gene expression and polymorphism by reverse transcriptase-polymerase chain reaction analysis and chemoresponse assay (ChemoFx®).

After completion of study therapy, patients are followed periodically for 10 years.

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Harry Bear, MD, PhD, Protocol chair		Ph: 804-828-9325 Email: hdbear@vcu.edu

U.S.A.
Michigan
	Lambertville
	Haematology-Oncology Associates of Ohio and Michigan, PC
		Paul Schaefer, MD	Ph:  419-479-5605
Ohio
	Bowling Green
	Wood County Oncology Center
		Paul Schaefer, MD	Ph:  419-479-5605
	Maumee
	Northwest Ohio Oncology Center
		Paul Schaefer, MD	Ph:  419-479-5605
		Paul Schaefer, MD	Ph:  419-479-5605
	St. Luke's Hospital
		Paul Schaefer, MD	Ph:  419-479-5605
	Oregon
	St. Charles Mercy Hospital
		Paul Schaefer, MD	Ph:  419-479-5605
	Toledo Clinic - Oregon
		Paul Schaefer, MD	Ph:  419-479-5605
	Sylvania
	Flower Hospital Cancer Center
		Clinical Trials Office - Flower Hospital Cancer Center	Ph:  419-824-1842
	Toledo
	CCOP - Toledo Community Hospital
		Paul Schaefer, MD	Ph:  419-479-5605
	Medical University of Ohio Cancer Center
		Clinical Trials Office - Medical University of Ohio Cancer Center	Ph:  419-383-6583
	St. Anne Mercy Hospital
		Paul Schaefer, MD	Ph:  419-479-5605
	St. Vincent Mercy Medical Center
		Paul Schaefer, MD	Ph:  419-479-5605
	Toledo Clinic, Incorporated - Main Clinic
		Paul Schaefer, MD	Ph:  419-479-5605
	Toledo Hospital
		Clinical Trials Office - Toledo Hospital	Ph:  419-824-1842

See All Trial Sites

Registry Information
Official Title		A Randomized Phase III Trial of Neoadjuvant Therapy in Patients with Palpable and Operable Breast Cancer Evaluating the Effect on Pathologic Complete Response (pCR) of Adding Capecitabine or Gemcitabine to Docetaxel when Administered Before AC With or Without Bevacizumab and Correlative Science Studies Attempting to Identify Predictors of High Likelihood for pCR with Each of the Regimens
Trial Start Date		2006-11-20
Trial Completion Date		2012-04-16 (estimated)
Registered in ClinicalTrials.gov		NCT00408408
Date Submitted to PDQ		2006-10-16
Information Last Verified		2010-02-09
NCI Grant/Contract Number		CA12027

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