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Summary

for people ages 18 years and up (full criteria)
at San Francisco, California and other locations
study started

Description

Summary

This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, and paclitaxel to see how well they work with or without bevacizumab in treating patients with cancer that has spread to the lymph nodes (lymph node-positive) or cancer that has not spread to the lymph nodes but is at high risk for returning (high-risk, lymph node-negative breast cancer). Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of breast cancer by blocking blood flow to the tumor. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery and help prevent the tumor from returning. It is not yet known whether doxorubicin hydrochloride, cyclophosphamide, and paclitaxel are more effective with or without bevacizumab.

Official Title

A Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer

Details

PRIMARY OBJECTIVES:

  1. 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:

  1. 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).

  1. 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.

  1. 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.

Keywords

Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Male Breast Carcinoma Stage IA Breast Cancer Stage IB Breast Cancer Stage IIA Breast Cancer Stage IIB Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Breast Neoplasms Breast Neoplasms, Male Paclitaxel Liposomal doxorubicin Albumin-Bound Paclitaxel Bevacizumab Cyclophosphamide Doxorubicin Endothelial Growth Factors Antibodies Immunoglobulins Antibodies, Monoclonal Immunoglobulin G

Eligibility

For people ages 18 years and up

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
  • Absolute neutrophil count >= 1,000/mm3

  • Platelet count >= 100,000/mm3

  • Total bilirubin =< 1.5 mg/dL
  • Aspartate aminotransferase (AST) =< 2 times upper limit of normal(ULN)
  • Serum creatinine =< 1.5 mg/dL
  • Urine protein:creatinine ratio < 1.0 or 24-hour protein
  • Partial thromboplastin time (PTT) =< 1.5 times ULN
  • Left ventricle ejection fraction (LVEF) >= institutional limits of normal by echocardiogram (ECHO) or multigated acquisition scan (MUGA)
  • 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

Locations

  • Zuckerberg San Francisco General Hospital
    San Francisco, California, 94110, United States
  • UCSF Medical Center-Mount Zion
    San Francisco, California, 94115, United States
  • California Pacific Medical Center-Pacific Campus
    San Francisco, California, 94115, United States
  • Kaiser Permanente-San Francisco
    San Francisco, California, 94115, United States
  • Cancer Care Associates of Fresno Medical Group Inc
    Fresno, California, 93720, United States
  • Kaiser Permanente-South San Francisco
    South San Francisco, California, 94080, United States
  • Bay Area Breast Surgeons Inc
    Emeryville, California, 94608, United States
  • Alta Bates Summit Medical Center - Summit Campus
    Oakland, California, 94609, United States
  • Bay Area Tumor Institute
    Oakland, California, 94609, United States
  • Hematology and Oncology Associates-Oakland
    Oakland, California, 94609, United States
  • Tom K Lee Inc
    Oakland, California, 94609, United States
  • Alta Bates Summit Medical Center-Herrick Campus
    Berkeley, California, 94704, United States
  • Marin Cancer Care Inc
    Greenbrae, California, 94904, United States
  • Marin General Hospital
    Greenbrae, California, 94904, United States
  • Highland General Hospital
    Oakland, California, 94602, United States
  • Kaiser Permanente-Richmond
    Richmond, California, 94801, United States
  • Mills-Peninsula Medical Center
    Burlingame, California, 94010, United States
  • Kaiser Permanente-Oakland
    Oakland, California, 94611, United States
  • Doctors Medical Center- JC Robinson Regional Cancer Center
    San Pablo, California, 94806, United States
  • Kaiser Permanente San Leandro
    San Leandro, California, 94577, United States
  • Kaiser Permanente-San Rafael
    San Rafael, California, 94903, United States
  • East Bay Radiation Oncology Center
    Castro Valley, California, 94546, United States
  • Eden Hospital Medical Center
    Castro Valley, California, 94546, United States
  • Valley Medical Oncology Consultants-Castro Valley
    Castro Valley, California, 94546, United States
  • Contra Costa Regional Medical Center
    Martinez, California, 94553-3156, United States
  • Kaiser Permanente-Redwood City
    Redwood City, California, 94063, United States
  • Kaiser Permanente-Walnut Creek
    Walnut Creek, California, 94596, United States
  • Sutter Cancer Research Consortium
    Novato, California, 94945, United States
  • Palo Alto Medical Foundation Health Care
    Palo Alto, California, 94301, United States
  • Stanford Cancer Institute Palo Alto
    Palo Alto, California, 94304, United States
  • Kaiser Permanente-Vallejo
    Vallejo, California, 94589, United States
  • Sutter Solano Medical Center/Cancer Center
    Vallejo, California, 94589, United States
  • Kaiser Permanente-Fremont
    Fremont, California, 94538, United States
  • Valley Medical Oncology Consultants-Fremont
    Fremont, California, 94538, United States
  • Washington Hospital
    Fremont, California, 94538, United States
  • Valley Care Health System - Pleasanton
    Pleasanton, California, 94588, United States
  • Valley Medical Oncology Consultants
    Pleasanton, California, 94588, United States
  • El Camino Hospital
    Mountain View, California, 94040, United States
  • Palo Alto Medical Foundation-Camino Division
    Mountain View, California, 94040, United States
  • Kaiser Permanente Medical Center - Santa Clara
    Santa Clara, California, 95051, United States
  • Kaiser Permanente-Deer Valley Medical Center
    Antioch, California, 94531, United States
  • Saint Helena Hospital
    Saint Helena, California, 94574, United States
  • Kaiser Permanente-Santa Teresa-San Jose
    San Jose, California, 95119, United States
  • Kaiser Permanente-Santa Rosa
    Santa Rosa, California, 95403, United States
  • Kaiser Permanente-Stockton
    Stockton, California, 95210, United States
  • Kaiser Permanente-South Sacramento
    Sacramento, California, 95823, United States
  • University of California Davis Comprehensive Cancer Center
    Sacramento, California, 95817, United States
  • Kaiser Permanente - Sacramento
    Sacramento, California, 95825, United States
  • Salinas Valley Memorial
    Salinas, California, 93901, United States
  • Community Hospital of Monterey Peninsula
    Monterey, California, 93940, United States
  • Kaiser Permanente-Roseville
    Roseville, California, 95661, United States
  • Fremont - Rideout Cancer Center
    Marysville, California, 95901, United States
  • PCR Oncology
    Pismo Beach, California, 93449, United States
  • Gene Upshaw Memorial Tahoe Forest Cancer Center
    Truckee, California, 96161, United States
  • Providence Saint Joseph Medical Center/Disney Family Cancer Center
    Burbank, California, 91505, United States
  • Glendale Memorial Hospital and Health Center
    Glendale, California, 91204, United States
  • USC / Norris Comprehensive Cancer Center
    Los Angeles, California, 90033, United States
  • Pomona Valley Hospital Medical Center
    Pomona, California, 91767, United States
  • University Medical Center of Southern Nevada
    Las Vegas, Nevada, 89102, United States
  • Nevada Cancer Research Foundation CCOP
    Las Vegas, Nevada, 89106, United States
  • Desert Regional Medical Center
    Palm Springs, California, 92262, United States
  • Eisenhower Medical Center
    Rancho Mirage, California, 92270, United States

Details

Status
in progress, not accepting new patients
Start Date
Sponsor
National Cancer Institute (NCI)
ID
NCT00433511
Phase
Phase 3
Study Type
Interventional
Last Updated
October 10, 2017