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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
North Central Cancer Treatment Group
Cancer and Leukemia Group B
Eastern Cooperative Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00433511
First received: February 8, 2007
Last updated: July 18, 2014
Last verified: May 2014
  Purpose

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


Condition Intervention Phase
Estrogen Receptor-negative Breast Cancer
Estrogen Receptor-positive Breast Cancer
HER2-negative Breast Cancer
Male Breast Cancer
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
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Drug: paclitaxel
Biological: bevacizumab
Other: placebo
Other: laboratory biomarker analysis
Other: quality-of-life assessment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Disease-free survival [ Time Frame: From the date of randomization to the date of first treatment failure, assessed up to 15 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: From randomization to date of death, assessed up to 15 years ] [ Designated as safety issue: No ]
    The comparison between arms will be made using a stratified log rank test among all randomized patients.

  • Incidence of adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Quality of life, measured by average total score for the Functional Assessment of Cancer Therapy-Breast [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    Compared between arms using a two-sided t-test. The Wilcoxon Rank Sum test will be used to compare the arms if the distributions of scores are not normally distributed. Longitudinal modeling will be used to look at changes in the scores over time across arms.


Other Outcome Measures:
  • Pharmacogenetic data [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    When data are available, they will be used for population stratification assessment. Then they will be correlated with efficacy and toxicity outcomes to identify single nucleotide polymorphism (SNP)/treatment interactions, i.e. SNPs that predict bevacizumab's efficacy and toxicity. Cox regression model for efficacy variables and the generalized linear model for toxicity outcome variables will be used. Additional gene ontology analyses will be performed to evaluate the functions of significant genes. Analysis for the association of toxicity with genotype will occur as results are reported.

  • Pharmacogenomic data [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    When data are available, they will be used for population stratification assessment. Then they will be correlated with efficacy and toxicity outcomes to identify single nucleotide polymorphism (SNP)/treatment interactions, i.e. SNPs that predict bevacizumab's efficacy and toxicity. Cox regression model for efficacy variables and the generalized linear model for toxicity outcome variables will be used. Additional gene ontology analyses will be performed to evaluate the functions of significant genes. Analysis for the association of toxicity with genotype will occur as results are reported.


Estimated Enrollment: 4950
Study Start Date: November 2007
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (chemotherapy, placebo)
Patients receive doxorubicin hydrochloride 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.
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Other: placebo
Given IV
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies (closed as of 5/28/10)
Other Name: quality of life assessment
Experimental: Arm II (chemotherapy, bevacizumab)
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.
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies (closed as of 5/28/10)
Other Name: quality of life assessment
Experimental: Arm III (chemotherapy, bevacizumab monotherapy)
Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I and bevacizumab as in arm II. Treatment repeats every 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.
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: quality-of-life assessment
Ancillary studies (closed as of 5/28/10)
Other Name: quality of life assessment

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • 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/mm^3
  • Platelet count >= 100,000/mm^3
  • Total bilirubin =< 1.5 mg/dL
  • Aspartate transferase (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 hybridisation [FISH] ratio >= 2) breast cancer are not eligible
  • Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00433511

  Show 825 Study Locations
Sponsors and Collaborators
North Central Cancer Treatment Group
Cancer and Leukemia Group B
Eastern Cooperative Oncology Group
Investigators
Principal Investigator: Kathy Miller ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00433511     History of Changes
Other Study ID Numbers: NCI-2009-00561, NCI-2009-00561, U10CA021115, ECOG-E5103, CDR0000528955, E5103, E5103, U10CA180820, U10CA021115
Study First Received: February 8, 2007
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms, Male
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies
Antibodies, Monoclonal
Cyclophosphamide
Bevacizumab
Doxorubicin
Paclitaxel
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents, Phytogenic
Angiogenesis Inhibitors
Angiogenesis Modulating Agents

ClinicalTrials.gov processed this record on July 24, 2014