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Doxorubicin Hydrochloride, Cy...

Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer

Last Updated: 2025-12-03

Study Results

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Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

4994 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-11-02

Study Completion Date

2026-02-22

Brief Summary

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PRIMARY OBJECTIVES:

I. To determine the disease-free survival of patients (defined as invasive disease-free survival \[IFDS\]) with lymph node positive and high risk lymph node negative breast cancer randomized to treatment with either doxorubicin (doxorubicin hydrochloride)/cyclophosphamide plus placebo followed by paclitaxel (AC + placebo \> T + placebo) or the same chemotherapy regimen plus bevacizumab.

SECONDARY OBJECTIVES:

I. To compare short-term (20-24 weeks) versus long-term (50-54 weeks) bevacizumab therapy.

II. To compare the overall survival. III. To evaluate toxicity. IV. To evaluate the association between outcomes in E5103 (disease-free survival, overall survival and toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome wide evaluations).

V. To compare the quality of life of breast cancer patients treated with AC/paclitaxel and bevacizumab or placebo, in terms of physical symptoms, physical functioning, psychological state and social functioning over an 18 month period.

VI. To determine the impact of theoretical biomarker information on patients' willingness to accept the toxicities of bevacizumab for the estimated potential benefit.

VII. To create a biospecimen repository including plasma, serum and CellSearch cassettes containing circulating tumor cells (CTC) for evaluating determinants of late relapse, including candidate biomarkers reflecting occult tumor burden (e.g., CTCs and plasma tumor deoxyribonucleic acid \[DNA\]) and host factors (e.g., estrogen, insulin-insulin-like growth factor \[IGF\] axis, inflammation, etc).

VIII. To create a biorepository of metastatic tumor samples in patients who have had a late relapse.

IX. To determine body mass index (BMI) and comorbidity burden in patients with operable breast cancer five or more years after diagnosis.

X. To determine whether there is a relationship between late relapse and BMI at diagnosis and at 5 years after diagnosis, and whether BMI-associated inflammatory and/or metabolic biomarkers are associated with early and late recurrence.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), cyclophosphamide IV over 20-30 minutes, and placebo IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel IV over 1 hour on days 1, 8, and 15 and placebo IV over 30-90 minutes on day 1. Treatment with paclitaxel and placebo repeats every 3 weeks for 4 courses.

ARM II: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses.

ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 2 or 3 weeks for 4 courses. Beginning 3 weeks later, patients then receive paclitaxel as in arm I and bevacizumab as in arm II. Treatment with paclitaxel and bevacizumab repeats every 3 weeks for 4 courses. Beginning 2 months later, patients then receive bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 15 years.

Conditions

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Breast Adenocarcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type OTHER

Ancillary studies (closed as of 5/28/10)

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WR138719 Bevacizumab-maly Bevacizumab-onbe Bevacizumab-tnjn BP102 BP102 Biosimilar CT P16 CT-P16 CTP16 Equidacent FKB 238 FKB-238 FKB238 HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer MB 02 MB-02 MB02 Mvasi MYL-1402O Onbevzi Oyavas PF 06439535 PF-06439535 PF06439535 QL1101 Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Vegzelma Zirabev (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Asta B 518 B 518 B-518 B518 Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR 138719 WR- 138719 WR-138719 ABP 215 ABP-215 ABP215 Alymsys Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Avzivi Aybintio BAT 1706 BAT-1706 BAT1706 BAT1706 Biosimilar Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BAT1706 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MB02 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar QL1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-adcd Bevacizumab-awwb Bevacizumab-aybi Bevacizumab-bvzr Bevacizumab-equi 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI) ADM Adriacin Adriamycin Adriamycin Hydrochloride Adriamycin PFS Adriamycin RDF ADRIAMYCIN, HYDROCHLORIDE Adriamycine Adriblastina Adriblastine Adrimedac Chloridrato de Doxorrubicina DOX DOXO-CELL Doxolem Doxorubicin HCl Doxorubicin.HCl Doxorubin Farmiblastina FI 106 FI-106 FI106 hydroxydaunorubicin Rubex Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat Quality of Life Assessment

Eligibility Criteria

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Inclusion Criteria

* Patients must have histologically confirmed adenocarcinoma of the breast at significant risk of distant recurrence based on at least one of the following criteria:

* For axillary lymph node positive disease:

* Involvement of at least one sentinel or axillary lymph node on routine histologic examination; patients with negative sentinel nodes and negative axillary nodes or involvement only demonstrated by immunohistochemistry are not eligible unless they meet one of the other eligibility criteria below
* NOTE: consider intramammary nodes as equivalent to axillary nodes for the purposes of eligibility and stratification
* For axillary lymph node negative disease:

* Estrogen receptor (ER) negative tumor \>= 1 cm
* ER+ tumor \>= 5 cm regardless of recurrence score
* ER+ tumor \>= 1 cm but \< 5 cm with a recurrence score \>= 11 (patients enrolled in the TAILORx trial are eligible)
* NOTE: axillary dissection is strongly encouraged in patients with lymph node involvement identified on sentinel node biopsy
* Patients must have completed definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, breast conservation surgery and axillary dissection or breast conservation surgery and sentinel node biopsy

* NOTE: breast conservation surgery includes lumpectomy, partial mastectomy, and excisional biopsy
* Margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ (DCIS); patients with resection margins positive for lobular carcinoma in situ (LCIS) are eligible
* Time from last surgery for breast cancer (breast conservation surgery, mastectomy, sentinel node biopsy, axillary dissection or re-excision of breast conservation surgery margins) to planned treatment start date must be \> 28 days and =\< 84 days
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Within =\< 8 weeks prior to randomization: Absolute neutrophil count \>= 1,000/mm\^3
* Within =\< 8 weeks prior to randomization: Platelet count \>= 100,000/mm\^3
* Within =\< 8 weeks prior to randomization: Total bilirubin =\< 1.5 mg/dL
* Within =\< 8 weeks prior to randomization: Aspartate aminotransferase (AST) =\< 2 times upper limit of normal(ULN)
* Within =\< 8 weeks prior to randomization: Serum creatinine =\< 1.5 mg/dL
* Within =\< 8 weeks prior to randomization: Urine protein:creatinine ratio \< 1.0 or 24-hour protein
* Within =\< 8 weeks prior to randomization: Partial thromboplastin time (PTT) =\< 1.5 times ULN
* Within =\< 8 weeks prior to randomization: Left ventricle ejection fraction (LVEF) \>= institutional limits of normal by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
* Patients who have undergone breast conservation surgery must receive radiation; prior to randomization, the investigator must specify the planned radiation technique:

* Whole breast radiation (WBRT) after chemotherapy
* Accelerated partial breast radiation (APBI) after chemotherapy
* Accelerated partial breast radiation (APBI) prior to chemotherapy
* NOTE: if APBI was completed prior to study entry, day 1 of protocol therapy must be at least 4 weeks after the completion of APBI
* Post-mastectomy radiation therapy (RT) is required for all patients with a primary tumor of \>= 5 cm or involvement of 4 or more lymph nodes; post-mastectomy RT may be administered at the investigator's discretion for all other mastectomy patients
* Patients with human epidermal growth factor receptor (HER)2 + (3+ by immunohistochemistry \[IHC\] or fluorescent in situ hybridization \[FISH\] ratio \>= 2) breast cancer are not eligible
* Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher tumor, node, metastasis (TNM) stage tumor meets the eligibility criteria for this trial
* Patients must not have clinical evidence of inflammatory disease or fixed axillary nodes at diagnosis
* Patients must not have received prior cytotoxic chemotherapy or hormonal therapy for this breast cancer; prior treatment with an anthracycline, anthracenedione or taxane for any condition is not allowed

* NOTE: prior use of tamoxifen for chemoprevention is allowed but must be discontinued at study entry; similarly, prior raloxifene use is allowed but must be discontinued at study entry
* Patients must not have had any major surgical procedure within 28 days of planned treatment start date

* NOTE: non-operative biopsy or placement of a vascular access device is not considered a major surgery
* Patients may not have had placement of a vascular access device within 24 hours of planned day 1 of treatment
* Patients must not have clinically significant cardiovascular or cerebrovascular disease, including:

* Any history of

* Cerebrovascular disease including transient ischemic attack (TIA), stroke or subarachnoid hemorrhage
* Ischemic bowel
* Within the last 12 months

* Myocardial infarction
* Unstable angina
* New York Heart Association (NYHA) class II or greater congestive heart failure
* Grade II or greater peripheral vascular disease
* Uncontrolled hypertension defined as systolic blood pressure (SBP) \> 160 or diastolic blood pressure (DBP) \> 90
* Uncontrolled or clinically significant arrhythmia
* NOTE: blood pressure must be obtained within =\< 8 weeks prior to randomization
* NOTE: patients with controlled atrial fibrillation are eligible
* Patients who require full-dose anticoagulation may enroll provided they meet the following criteria:

* The patient must have an in-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of warfarin or be on stable dose of low molecular weight (LMW) heparin
* The patient must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. varices)
* NOTE: prophylactic use of anticoagulants to maintain patency of a vascular access device is permitted
* Patients must not have a bleeding diathesis, hereditary or acquired bleeding disorder or coagulopathy
* Patients must not have a non-healing wound or fracture; patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization are not eligible
* Patients must not have hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies
* Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood or urine test within 7 days prior to randomization to rule out pregnancy
* Women of childbearing potential and sexually active males must use an accepted and effective method of contraception

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers