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Clinical Trials (PDQ®)

  • First Published: 2/5/2007
  • Last Modified: 7/17/2012

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Clinical Trials (PDQ®)

Phase III Randomized Study of Adjuvant Therapy Comprising Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With Versus Without Bevacizumab in Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer

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

Alternate Title

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed18 and overNCIECOG-E5103
E5103, NCT00433511

Special Category: CTSU trial

Objectives

Primary

  1. 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

  1. Compare the overall survival of patients treated with these regimens.
  2. Determine the toxicity of these regimens.
  3. Compare the efficacy of short-term (20-24 weeks) vs long-term (50-54 weeks) bevacizumab, in terms of DFS, in these patients.
  4. Evaluate the association between outcomes (disease-free survival, overall survival and toxicities) and genotype (derived from candidate single nucleotide polymorphisms and genome wide evaluations).
  5. 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. (QOL closed as of 05/28/10)
  6. Determine the impact of theoretical biomarker information on patients’ willingness to accept the toxicities of bevacizumab for the estimated potential benefit.

Entry 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

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

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 or 24-hour protein
  • 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

Expected Enrollment

4950

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

Outcomes

Primary Outcome(s)

Disease-free survival (DFS)

Secondary Outcome(s)

Efficacy of short-term vs long-term bevacizumab, in terms of DFS
Overall survival
Quality of life patients in terms of physical symptoms, physical functioning, psychological state and social functioning over 18 months (QOL closed as of 05/28/10)
Theoretical biomarker information impact on acceptance of bevacizumab toxicities for 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. (QOL closed as of 05/28/10)

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

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Kathy Miller, MD, Protocol chair
Ph: 317-274-1690; 888-600-4822
Email: kathmill@iupui.edu
Ramona Swaby, MD, Protocol co-chair
Ph: 215-728-0417; 888-369-2427

North Central Cancer Treatment Group

Donald Northfelt, MD, FACP, Protocol chair
Ph: 507-538-7623
Email: cancerclinicaltrials@mayo.edu

Cancer and Leukemia Group B

Chau Dang, MD, Protocol co-chair
Ph: 212-639-5426; 800-525-2225

Related Information

PDQ® clinical trial NCI-2009-00707

Registry Information
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
Trial Start Date 2007-11-02
Trial Completion Date 2016-09-30 (estimated)
Registered in ClinicalTrials.gov NCT00433511
Date Submitted to PDQ 2006-12-27
Information Last Verified 2011-02-28
NCI Grant/Contract Number CA21115

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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