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Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00005970
First Posted: January 27, 2003
Last Update Posted: August 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Cancer and Leukemia Group B
Eastern Cooperative Oncology Group
Canadian Cancer Trials Group
Southwest Oncology Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
July 5, 2000
January 27, 2003
August 22, 2017
May 19, 2000
November 15, 2009   (Final data collection date for primary outcome measure)
Duration of DFS [ Time Frame: Time from registration to first adverse event, assessed up to 15 years ]
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.
Not Provided
Complete list of historical versions of study NCT00005970 on ClinicalTrials.gov Archive Site
Overall survival [ Time Frame: Time from registration to death due to any cause, assessed up to 15 years ]
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.
Not Provided
Not Provided
Not Provided
 
Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer
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
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the lymph nodes. 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.

PRIMARY OBJECTIVES:

I. To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare the combination of AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events. (Stage I) III. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)

SECONDARY OBJECTIVES:

I. To compare the combination of AC followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall survival (OS).

II. To compare the combination AC followed by weekly paclitaxel with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

TERTIARY OBJECTIVES:

I. To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to treatment are prognostic for DFS and survival.

II. To determine the concordance of central review of HER-2 overexpression as measured by the HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).

III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT), troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.

IV. To determine whether genetic markers are prognostic for cardiac adverse events associated with treatment.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I*: Patients receive doxorubicin hydrochloride intravenously (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. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

ARM II*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab 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. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

ARM III: 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 estrogen receptor (ER)- or progesterone receptor (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.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually for 15 years or until disease progression.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • 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: Aromatase Inhibition Therapy
    Given orally
    Other Name: Aromatase Inhibition
  • Drug: Cyclophosphamide
    Given IV
  • Drug: Doxorubicin Hydrochloride
    Given IV
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Paclitaxel
    Given IV
  • Drug: Tamoxifen Citrate
    Given orally
  • Biological: Trastuzumab
    Given IV
  • 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.
    Interventions:
    • Drug: Aromatase Inhibition Therapy
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Drug: Tamoxifen Citrate
  • 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.
    Interventions:
    • Drug: Aromatase Inhibition Therapy
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Drug: Tamoxifen Citrate
    • Biological: Trastuzumab
  • 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.

    Interventions:
    • Drug: Aromatase Inhibition Therapy
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Drug: Tamoxifen Citrate
    • Biological: Trastuzumab

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
3441
Not Provided
November 15, 2009   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: Female
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Canada,   Peru,   South Africa,   United States
 
 
NCT00005970
NCI-2012-01849
NCI-2012-01849 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ECOG-N9831
CAN-NCIC-MA28
SWOG-N9831
MA.28
NCCTG-N9831
CALGB-49909
CDR0000067953
GUMC-00224
N9831 ( Other Identifier: Alliance for Clinical Trials in Oncology )
N9831 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA025224 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
  • Cancer and Leukemia Group B
  • Eastern Cooperative Oncology Group
  • Canadian Cancer Trials Group
  • Southwest Oncology Group
Principal Investigator: Edith Perez Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP