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Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Eastern Cooperative Oncology Group
Cancer and Leukemia Group B
Southwest Oncology Group
NCIC Clinical Trials Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00005970
First received: July 5, 2000
Last updated: February 27, 2015
Last verified: December 2014
  Purpose

This randomized phase III trial studies combination chemotherapy and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without trastuzumab in treating breast cancer.


Condition Intervention Phase
Breast Adenocarcinoma
HER2 Positive Breast Carcinoma
Stage IA Breast Cancer
Stage IB Breast Cancer
Stage IIA Breast Cancer
Stage IIB Breast Cancer
Stage IIIA Breast Cancer
Drug: Doxorubicin Hydrochloride
Drug: Cyclophosphamide
Drug: Paclitaxel
Biological: Trastuzumab
Drug: Tamoxifen Citrate
Drug: Aromatase Inhibition Therapy
Other: Laboratory Biomarker Analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-Expressing or Amplified Node Positive or High-Risk Node Negative Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Duration of DFS [ Time Frame: Time from registration to first adverse event, assessed up to 15 years ] [ Designated as safety issue: No ]
    Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether DFS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for DFS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: Time from registration to death due to any cause, assessed up to 15 years ] [ Designated as safety issue: No ]
    Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether OS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for OS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.


Estimated Enrollment: 3000
Study Start Date: May 2000
Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)
Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Drug: Doxorubicin Hydrochloride
Given IV
Drug: Cyclophosphamide
Given IV
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • TAX
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • ICI 46,474
  • ICI-46474
Drug: Aromatase Inhibition Therapy
Given orally
Other Name: Aromatase Inhibition
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm II (AC, paclitaxel, trastuzumab, tamoxifen)
Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) IV over 30-90 minutes beginning on day 1 of week 25 and continuing weekly for 52 courses in the absence of disease progression or unacceptable toxicity. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.
Drug: Doxorubicin Hydrochloride
Given IV
Drug: Cyclophosphamide
Given IV
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • TAX
Biological: Trastuzumab
Given IV
Other Names:
  • ABP 980
  • PF-05280014
  • rhuMAb HER2
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • ICI 46,474
  • ICI-46474
Drug: Aromatase Inhibition Therapy
Given orally
Other Name: Aromatase Inhibition
Other: Laboratory Biomarker Analysis
Correlative studies
Experimental: Arm III (AC, paclitaxel, trastuzumab, tamoxifen)

Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I. Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40 courses in the absence of disease progression or unacceptable toxicity.

Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or PR-positive patients receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until they have received a total of 5 years of adjuvant hormonal therapy.

Drug: Doxorubicin Hydrochloride
Given IV
Drug: Cyclophosphamide
Given IV
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • TAX
Biological: Trastuzumab
Given IV
Other Names:
  • ABP 980
  • PF-05280014
  • rhuMAb HER2
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • ICI 46,474
  • ICI-46474
Drug: Aromatase Inhibition Therapy
Given orally
Other Name: Aromatase Inhibition
Other: Laboratory Biomarker Analysis
Correlative studies

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Required tumor parameters for node positive disease: NOTE: This study will continue to use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification and staging

    • Operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes

      • Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by hematoxylin and eosin (H&E)

        • NOTE: Positive nodes refers to H&E visible nodal metastases; immunohistochemistry (IHC) positive only cells in lymph nodes will not be considered positive nodes
      • One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are eligible
      • cN2 disease is not eligible
      • pN2 disease is eligible
      • One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least one positive lymph node
      • Metaplastic carcinoma is eligible
    • ER/PgR determination
    • HER-2 positive (pre-entry requirement for registration)

      • FISH must show gene amplification OR
      • IHC assay must show a strong positive (3+) staining score

        • NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification
  • Required tumor parameters for high-risk node-negative disease; NOTE: This study will continue to use the AJCC 5th edition for TNM classification and staging

    • Operable, histologically confirmed adenocarcinoma of the female breast and negative lymph nodes

      • Node status may be determined by either axillary node dissection or sentinel node biopsy with H&E staining; to be considered node negative, either of the following must be true: 1) negative sentinel node biopsy or 2) no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection
      • NOTE: IHC positive only cells in lymph nodes will not be considered positive nodes
      • Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if ER-negative and PR-negative disease
    • ER/PgR determination
    • HER-2 positive (pre-entry requirement for registration)

      • FISH must show gene amplification OR
      • IHC assay must show a strong positive (3+) staining score

        • NOTE: DCIS components should not be counted in the determination of degree of IHC staining or FISH amplification
  • =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node detection if the patient's most extensive breast surgery was a breast sparing procedure; (This timing is per a decision by the Breast Intergroup)
  • Surgical resection margins. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy with axillary node dissection

    • Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or DCIS) at the surgical resection margins noted in the final surgery or pathology reports; patients with close margins are eligible
    • Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and DCIS
    • Axillary dissection or sentinel node dissection: There will be no gross residual adenopathy
  • TAM therapy

    • May have received up to four weeks of TAM therapy, or any other hormonal agent, for this malignancy
    • May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before registration on this study
    • May never have received TAM, raloxifene, or any other hormonal agent
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets (PLT) >= 100,000/mm^3
  • Total bilirubin =< 1.5 x upper normal limit (UNL)
  • Aspartate aminotransferase (AST) =< 2.0 x UNL
  • Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF is > 75%, the investigator should consider performing a second review of the multigated acquisition (MUGA)/echocardiogram or performing a repeat MUGA/echocardiogram prior to registration; such re-reviews or repeat MUGA/echocardiogram are not permitted after registration
  • Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc., prior to registration and while on study
  • Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to registration and while on study
  • Non-breast malignancies that have not recurred within the last 5 years and are deemed to be at low risk for recurrence

EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior to registration:

  • Squamous or basal cell carcinoma of the skin that has been effectively treated
  • Carcinoma in situ of the cervix that has been treated by surgery only
  • Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by surgery and/or tamoxifen only

    • Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary dissection) must have plans to receive radiation therapy to the breast +/- regional lymphatics following completion of the chemotherapy; for patients treated with mastectomy, the use of radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy; the use of radiation therapy is at the discretion of the investigator for 0-3 positive lymph nodes but, if used, must be started after the completion of chemotherapy
    • Prior to registration, the physician must designate if it is planned for the patient to receive radiation therapy (for adjuvant radiation therapy post-mastectomy or, less commonly, post-conservative therapy but not primary breast radiation as part of breast conserving treatment)
    • Willing and able to sign an informed consent
    • Gene amplified by FISH or strong positivity (3+) by HercepTest on central review; Note: The patient registers based on community HER-2 testing using FISH or IHC, AC chemotherapy is initiated; the tumor block or slides must be received =< 2 weeks from time of registration to the North Central Cancer Treatment Group (NCCTG) Operations Office for central HER-2 testing

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, intrauterine device [IUD], surgical sterilization, or abstinence, etc.); hormonal birth control methods are not permitted
  • Locally advanced tumors (classification T4) at diagnosis including tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
  • Prior history of breast cancer, except LCIS
  • Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of the contralateral breast treated with mastectomy are eligible)
  • Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer
  • Active, unresolved infection
  • Active cardiac disease

    • Any prior myocardial infarction
    • History of documented congestive heart failure (CHF)
    • Current use of digitalis or beta-blockers for CHF
    • Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant
    • Current use of medications for treatment of arrhythmias or angina pectoris
    • Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)
    • Clinically significant pericardial effusion
  • Prior anthracycline or taxane therapy for any malignancy
  • Sensitivity to benzyl alcohol
  • Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's) Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will be looked at on a case-by-case basis by the study chair
  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: NCT00005970

  Show 158 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
Cancer and Leukemia Group B
Southwest Oncology Group
NCIC Clinical Trials Group
Investigators
Principal Investigator: Edith Perez Alliance for Clinical Trials in Oncology
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00005970     History of Changes
Other Study ID Numbers: NCI-2012-01849, NCI-2012-01849, ECOG-N9831, CAN-NCIC-MA28, SWOG-N9831, MA.28, CALGB-49909, NCCTG-N9831, CDR0000067953, GUMC-00224, N9831, N9831, U10CA025224, U10CA180821
Study First Received: July 5, 2000
Last Updated: February 27, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Aromatase Inhibitors
Cyclophosphamide
Doxorubicin
Liposomal doxorubicin
Paclitaxel
Tamoxifen
Trastuzumab
Alkylating Agents
Antibiotics, Antineoplastic
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Hormonal
Antineoplastic Agents, Phytogenic
Antirheumatic Agents
Bone Density Conservation Agents
Enzyme Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 01, 2015