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

Sponsor:	Eastern Cooperative Oncology Group
Collaborators:	National Cancer Institute (NCI) North Central Cancer Treatment Group Cancer and Leukemia Group B
Information provided by:	Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:	NCT00433511

Purpose

RATIONALE: 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.

PURPOSE: This randomized phase III trial is studying 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.

Condition	Intervention	Phase
Breast Cancer	Biological: bevacizumab Drug: cyclophosphamide Drug: paclitaxel Drug: pegylated liposomal doxorubicin hydrochloride Other: placebo	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Placebo Control
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:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Surgery

Drug Information available for: Cyclophosphamide Doxorubicin Doxorubicin hydrochloride Paclitaxel Bevacizumab

U.S. FDA Resources

Further study details as provided by Eastern Cooperative Oncology Group:

Primary Outcome Measures:

Disease-free survival (DFS) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Efficacy of short-term vs long-term bevacizumab, in terms of DFS [ Designated as safety issue: No ]
Overall survival [ Designated as safety issue: No ]
Quality of life patients in terms of physical symptoms, physical functioning, psychological state and social functioning over 18 months [ Designated as safety issue: No ]
Theoretical biomarker information impact on acceptance of bevacizumab toxicities for potential benefit [ Designated as safety issue: No ]

Estimated Enrollment:	4950
Study Start Date:	November 2007
Estimated Primary Completion Date:	November 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I: Active Comparator 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: cyclophosphamide Given IV Drug: paclitaxel Given IV Drug: pegylated liposomal doxorubicin hydrochloride Given IV Other: placebo Given IV over 30-90 minutes
Arm II: Experimental 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.	Biological: bevacizumab Given IV Drug: cyclophosphamide Given IV Drug: paclitaxel Given IV Drug: pegylated liposomal doxorubicin hydrochloride Given IV
Arm III: Experimental 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 open-label bevacizumab IV over 30-90 minutes on day 1. Treatment with bevacizumab alone repeats every 3 weeks for 10 courses.	Biological: bevacizumab Given IV Drug: cyclophosphamide Given IV Drug: paclitaxel Given IV Drug: pegylated liposomal doxorubicin hydrochloride Given IV

Detailed Description:

OBJECTIVES:

Primary

Compare the disease-free survival (DFS) of patients with lymph node-positive or high-risk, lymph node-negative breast cancer treated with adjuvant therapy comprising doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with vs. without bevacizumab.

Secondary

Compare the overall survival of patients treated with these regimens.
Determine the toxicity of these regimens.
Compare the efficacy of short-term (20-24 weeks) vs long-term (50-54 weeks) bevacizumab, in terms of DFS, in these patients.
Evaluate the association between outcomes (disease-free survival, overall survival and toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome wide evaluations).
Compare quality of life patients treated with these regimens, in terms of physical symptoms, physical functioning, psychological state and social functioning over an 18 month period.
Determine the impact of theoretical biomarker information on patients' willingness to accept the toxicities of bevacizumab for the estimated potential benefit.

OUTLINE: This is a randomized, partially double-blind, placebo-controlled, partially open-label, multicenter study. Patients are stratified according to planned dose schedule of doxorubicin hydrochloride and cyclophosphamide (every 3 weeks vs every 2 weeks). Patients are further stratified according to estrogen receptor status (positive vs negative), lymph node involvement (node-negative vs 1-3 positive node[s] vs ≥ 4 positive nodes), and received/planned treatment (lumpectomy and whole breast radiation therapy vs lumpectomy and accelerated partial-breast radiation therapy [before or after chemotherapy] vs mastectomy without radiation therapy vs mastectomy [with local or regional]). Patients are randomized to 1 of 3 treatment arms (20% of patients are randomized to Arm I, 40% to Arm II, and 40% to Arm III).

Arm I: 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.
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 open-label 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. Patients complete quality of life (QOL) questionnaires followed by telephone QOL interviews at baseline and periodically.

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

PROJECTED ACCRUAL: A total of 4,950 patients will be accrued for this study.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the breast
- Significant risk of distant recurrence based on ≥ 1 of the following criteria:
  - Axillary lymph node positive disease
    - At least 1 sentinal or axillary lymph node (LN) positive on routine histologic examination (must be demonstrated by more than immunohistochemistry alone)
    - Intramammary nodes considered equivalent to axillary nodes
  - Axillary lymph node negative disease
    - LN negative with estrogen receptor (ER)-negative tumor ≥ 1 cm
    - LN negative with ER+ tumor ≥ 5 cm regardless of recurrence score
    - LN negative with ER+ tumor ≥ 1 cm but < 5 cm with a recurrence score ≥ 11
      - Patients enrolled on ECOG-PACCT-1 clinical trial are eligible
Has undergone definitive breast surgery within the past 29-84 days, including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, lumpectomy and axillary dissection, or lumpectomy and sentinel node biopsy
- Surgical margins must be histologically free of invasive breast cancer and ductal carcinoma in situ
  - Resection margins positive for lobular carcinoma in situ allowed
Planned post-lumpectomy radiation therapy required, including any of the following:
- Whole breast radiation therapy after chemotherapy
- Accelerated partial breast radiation therapy after chemotherapy
- Accelerated partial breast radiation therapy prior to chemotherapy
Planned post-mastectomy radiation therapy required for patients with a primary tumor of ≥ 5 cm or involvement of ≥ 4 lymph nodes
No HER2/neu positive breast cancer (i.e., 3+ by immunohistochemistry or fluorescent in situ hybridization [FISH] ratio ≥ 2)
No clinical evidence of inflammatory disease or fixed axillary nodes (N2) at diagnosis
May have synchronous bilateral breast cancer (diagnosed ≤ 1 month) if the higher TNM stage tumor meets the eligibility criteria for this trial
Hormone receptor status known

PATIENT CHARACTERISTICS:

Male or female
Pre- or post-menopausal
ECOG performance status 0-1
Absolute neutrophil count ≥ 1,000/mm³
Platelet count ≥ 100,000/mm³
Bilirubin ≤ 1.5 mg/dL
AST ≤ 2 times upper limit of normal (ULN)
Creatinine ≤ 1.5 mg/dL
Urine protein:creatinine ratio < 1.0
PTT ≤ 1.5 times ULN
LVEF normal by echocardiogram or MUGA
No clinically significant cardiovascular or cerebrovascular disease, including any of the following:
- Uncontrolled arrhythmia
  - Controlled atrial fibrillation allowed
- Uncontrolled hypertension, defined as systolic blood pressure (BP) > 160 mm Hg or diastolic BP > 90 mm Hg
- Transient ischemic attack, stroke, or subarachnoid hemorrhage
- Ischemic bowel
- Myocardial infarction within the past 12 months
- Unstable angina within the past 12 months
- New York Heart Association class II-IV congestive heart failure within the past 12 months
- Peripheral vascular disease ≥ grade 2 within the past 12 months
No bleeding diathesis, hereditary or acquired bleeding disorder, or coagulopathy
No nonhealing wound or fracture
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No hypersensitivity to paclitaxel or drugs using the vehicle Cremophor EL, Chinese hamster ovary cell products, or other recombinant human antibodies
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
More than 28 days since prior major surgery
- Nonoperative biopsy not considered major surgery
More than 24 hours since prior placement of a vascular access device
No prior cytotoxic chemotherapy or hormonal therapy for study cancer
- May have received prior (but no concurrent) tamoxifen or raloxifene for chemoprevention
No prior anthracycline, anthracenedione, or taxane for any condition
Concurrent full-dose anticoagulation allowed provided the following criteria are met:
- INR in-range (usually between 2 and 3) on a stable dose of warfarin or low molecular weight heparin
- No active bleeding or pathological conditions that carry a high risk of bleeding (e.g., varices)
Concurrrent prophylactic anticoagulants to maintain patency of a vascular access device allowed
No concurrent cardioprotectant drugs

Contacts and Locations

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

Show 713 Study Locations

Sponsors and Collaborators

Eastern Cooperative Oncology Group

National Cancer Institute (NCI)

North Central Cancer Treatment Group

Cancer and Leukemia Group B

Investigators

Study Chair:	Kathy Miller, MD	Indiana University Melvin and Bren Simon Cancer Center
Investigator:	Ramona Swaby, MD	Fox Chase Cancer Center
Study Chair:	Donald W. Northfelt, MD, FACP	Mayo Clinic
Investigator:	Chau T. Dang, MD	Memorial Sloan-Kettering Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	ECOG Group Chair's Office ( Robert L. Comis )
Study ID Numbers:	CDR0000528955, U10CA021115, ECOG-E5103
Study First Received:	February 8, 2007
Last Updated:	January 15, 2010
ClinicalTrials.gov Identifier:	NCT00433511 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Eastern Cooperative Oncology Group:

male breast cancer
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer

Additional relevant MeSH terms:

Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Bevacizumab
Cyclophosphamide
Antibiotics, Antineoplastic
Neoplasms by Site
Therapeutic Uses
Growth Inhibitors
Angiogenesis Modulating Agents
Alkylating Agents
Breast Diseases
Skin Diseases
Growth Substances

Mitosis Modulators
Breast Neoplasms
Antimitotic Agents
Angiogenesis Inhibitors
Immunosuppressive Agents
Pharmacologic Actions
Doxorubicin
Neoplasms
Paclitaxel
Tubulin Modulators
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on February 08, 2010