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NCT00513292 · CITED IN SOURCE DOCUMENTS

Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2019-01-23

This randomized phase III trial is studying giving fluorouracil together with epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab to see how well it works compared with giving paclitaxel together with trastuzumab followed by fluorouracil, epirubicin, cyclophosphamide, and trastuzumab in treating women with palpable breast cancer that can be removed by surgery. Drugs used in chemotherapy 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 trastuzumab, 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. It is not yet known whether it is more effective to give combination chemotherapy before or after treatment with paclitaxel plus trastuzumab.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy

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outcome · POSTED

Combined pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy

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outcome · POSTED

Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12

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outcome · POSTED

Asymptomatic Decreases From Baseline in LVEF at Week 24

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outcome · POSTED

LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week

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outcome · POSTED

Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week

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outcome · POSTED

Breast Conservation

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outcome · POSTED

Disease-free Survival (DFS)

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outcome · POSTED

Overall Survival (OS)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Diagnosis of invasive adenocarcinoma by core needle biopsy * Fine needle aspiration allowed provided primary tumor size \< 2 cm and lymph node metastases are present * Excisional biopsy of the primary tumor allowed provided biopsy-positive lymph nodes are present * Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node * HER2-positive disease * Confirmation by fluorescent in situ hybridization (FISH) requires gene amplification * Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+) staining intensity score * Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed * Synchronous invasive breast cancer not allowed * Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed * Those treated with radiation therapy are not allowed * No definitive clinical or radiologic evidence of metastatic disease * No history of invasive breast cancer * Hormone receptor status known * Menopausal status not specified * ECOG performance status of 0 -1 * Absolute neutrophil count ≥ 1,200/mm³ * Platelet count ≥ 100,000/mm³ * Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to 1.5 times upper limit of normal \[ULN\]) resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin * Alkaline phosphatase ≤ 2.5 times ULN * AST ≤ 1.5 times ULN * Creatinine normal * Left ventricular ejection fraction (LVEF) ≥ 55 by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) within the past 3 months * Patients with either skeletal pain or alkaline phosphatase that is \> ULN but ≤ 2.5 times ULN allowed if bone scans fail to demonstrate metastatic disease * Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy * Prior non-breast malignancies allowed if disease-free for 5 years since completion of initial treatment regimen and deemed by their physician to be at low risk for recurrence * Patients who had the following cancers are eligible if diagnosed and treated within the past 5 years: * Carcinoma in situ of the cervix * Colon carcinoma in situ * Melanoma in situ * Basal cell and squamous cell carcinoma of the skin * No cardiac disease that would preclude the use of epirubicin hydrochloride or trastuzumab (Herceptin®) including any of the following: * Active cardiac disease * Angina pectoris that requires the use of antianginal medication * Cardiac arrhythmia requiring medication * Severe conduction abnormality * Clinically significant valvular disease * Cardiomegaly on chest x-ray * Ventricular hypertrophy on EKG * Patient's with poorly controlled hypertension ( i.e., diastolic greater than 100 mm/Hg) * Patients with hypertension that is well controlled on medication are eligible * History of cardiac disease * Myocardial infarction documented as a clinical diagnosis or by EKG or any other tests * Documented congestive heart failure * Documented cardiomyopathy * No sensory or motor neuropathy ≥ grade 2, as defined by the NCI's CTCAE v3.0 * Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy * Women of child bearing potential must have a negative urine or serum pregnancy test within 2 weeks of registration * Not pregnant or nursing * No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements * No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would preclude treatment with either of the treatment regimens * No prior surgical axillary staging procedure * Prior non-excisional biopsy of an axillary node allowed * No prior treatment for this breast cancer * Hormonal therapy allowed if had been given for up to a total of 28 days anytime after diagnosis and before study entry * Hormonal therapy must stop at or before study entry and be re-started, if indicated, following surgery * No prior therapy with anthracyclines or taxanes for any malignancy * No other investigational agents within the past 30 days * No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal replacement therapy) * No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention
healthy Volunteers
false
minimum Age
18 Years
sex
FEMALE
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Patients receive FEC comprising fluoroucacil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.
    intervention Names
    1. Drug: Cyclophosphamide
    2. Drug: Epirubicin Hydrochloride
    3. Other: Laboratory Biomarker Analysis
    4. Drug: Paclitaxel
    5. Procedure: Therapeutic Conventional Surgery
    6. Biological: Trastuzumab
    label
    FEC-75 then Paclitaxel/trastuzumab
    type
    ACTIVE_COMPARATOR
  2. description
    Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I.
    intervention Names
    1. Drug: Cyclophosphamide
    2. Drug: Epirubicin Hydrochloride
    3. Other: Laboratory Biomarker Analysis
    4. Drug: Paclitaxel
    5. Procedure: Therapeutic Conventional Surgery
    6. Biological: Trastuzumab
    label
    Paclitaxel/trastuzumab then trastuzumab/FEC-75
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Given IV
    name
    Cyclophosphamide
    other Names
    1. (-)-Cyclophosphamide
    2. 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    3. Carloxan
    4. Ciclofosfamida
    5. Ciclofosfamide
    6. Cicloxal
    7. Clafen
    8. Claphene
    9. CP monohydrate
    10. CTX
    11. CYCLO-cell
    12. Cycloblastin
    type
    DRUG
  2. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Given IV
    name
    Epirubicin Hydrochloride
    other Names
    1. Ellence
    2. IMI-28
    3. Pharmorubicin PFS
    type
    DRUG
  3. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Correlative studies
    name
    Laboratory Biomarker Analysis
    type
    OTHER
  4. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Given IV
    name
    Paclitaxel
    other Names
    1. Anzatax
    2. Asotax
    3. Bristaxol
    4. Praxel
    5. Taxol
    6. Taxol Konzentrat
    type
    DRUG
  5. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Undergo surgery
    name
    Therapeutic Conventional Surgery
    type
    PROCEDURE
  6. arm Group Labels
    1. FEC-75 then Paclitaxel/trastuzumab
    2. Paclitaxel/trastuzumab then trastuzumab/FEC-75
    description
    Given IV
    name
    Trastuzumab
    other Names
    1. ABP 980
    2. Anti-c-ERB-2
    3. Anti-c-erbB2 Monoclonal Antibody
    4. Anti-ERB-2
    5. Anti-erbB-2
    6. Anti-erbB2 Monoclonal Antibody
    7. Anti-HER2/c-erbB2 Monoclonal Antibody
    8. Anti-p185-HER2
    9. c-erb-2 Monoclonal Antibody
    10. HER2 Monoclonal Antibody
    11. Herceptin
    12. Herceptin Biosimilar PF-05280014
    type
    BIOLOGICAL
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
280
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    Pathological complete response (pCR) rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review of these institutional pathology reports. The Chi-squared test will be conducted at the two-sided 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates.
    measure
    pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy
    time Frame
    Up to 5 years
secondary Outcomes
  1. description
    pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy (among those with Metastasis to movable ipsilateral axillary lymph node(s) (cN1-3) disease).
    measure
    Combined pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy
    time Frame
    Up to 5 years
  2. description
    The summary of asymptomatic decrease in LVEF.
    measure
    Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12
    time Frame
    Baseline, at 12 week
  3. description
    The summary of asymptomatic changed in LVEF.
    measure
    Asymptomatic Decreases From Baseline in LVEF at Week 24
    time Frame
    Baseline, at 24 week
  4. description
    All patients who had a MUGA or ECHO performed at week 12 are included in the summary of asymptomatic changed in LVEF at week 12. Difference from pretreatment LVEF (%) at 12 weeks \[median change from baseline Inter Quartile Range (IQR)\].
    measure
    LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week
    time Frame
    At 12 week
  5. description
    Difference from pretreatment LVEF (%) at 24 weeks \[median change from baseline Inter Quartile Range (IQR)\].
    measure
    Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week
    time Frame
    Baseline, at 24 week
  6. description
    Surgery was categorized as breast conserving surgery ("Partial Mastectomy") or non-conserving surgery ("Total Mastectomy" or "Modified Radical Mastectomy). Reported below is the percentage of patients receiving "Partial Mastectomy". This was calculated by dividing the number of patients receiving "Partial Mastectomy" by the total number of patients undergoing surgery multiplied by 100 (to obtain the percentage).
    measure
    Breast Conservation
    time Frame
    From time surgery to up to 5 years
  7. description
    DFS defined as inoperable progressive disease, gross residual disease following definitive surgery, local, regional or distant recurrence, contralateral breast cancer, other second primary cancers, and death prior to recurrence or second primary cancer. DFS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.
    measure
    Disease-free Survival (DFS)
    time Frame
    From time to registration to time of event, assessed up to 5 years
  8. description
    OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.
    measure
    Overall Survival (OS)
    time Frame
    From time to registration to death, assessed up to 5 years
Full study description
brief Summary
This randomized phase III trial is studying giving fluorouracil together with epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab to see how well it works compared with giving paclitaxel together with trastuzumab followed by fluorouracil, epirubicin, cyclophosphamide, and trastuzumab in treating women with palpable breast cancer that can be removed by surgery. Drugs used in chemotherapy 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 trastuzumab, 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. It is not yet known whether it is more effective to give combination chemotherapy before or after treatment with paclitaxel plus trastuzumab.
detailed Description
PRIMARY OBJECTIVES: I. The primary objective of this study is to compare the pathologic complete response rate (pCR) within the breast of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75 (Arm 2), to the pCR rate of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab (Arm 1). SECONDARY OBJECTIVES: I. To estimate the cardiotoxicity of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75, followed postoperatively by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 2), and compare the cardiotoxicity to that of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab, followed by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 1). II. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study. III. To compare the clinical response rates (cRR) of the two regimens evaluated in this study. IV. To compare the non-cardiac toxicity of the two regimens evaluated in this study. V. To compare breast conservation rates achieved with the two regimens evaluated in this study. VI. To evaluate disease-free survival and overall survival at 5 years post-randomization. VII. To correlate pCR rate with potential molecular markers of response. OUTLINE: Patients are stratified by clinical tumor size (breast tumor size \< 2 cm and nodal metastases \< 2 cm vs breast tumor size \< 2 cm and nodal metastases ≥ 2 cm vs breast tumor size 2-4 cm \[any nodal status\] vs breast tumor size ≥ 4 cm \[any nodal status\]), age (\< 50 vs ≥ 50) and hormone receptor status (estrogen receptor \[ER\]- and progesterone receptor \[PgR\]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive FEC comprising fluoroucacil intravenously (IV), epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks. ARM II: Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I. After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 4 years.
Source references
references
  1. citation
    Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. doi: 10.1001/jamaoncol.2018.3691.
    pmid
    30193295
    type
    DERIVED
  2. citation
    Lesurf R, Griffith OL, Griffith M, Hundal J, Trani L, Watson MA, Aft R, Ellis MJ, Ota D, Suman VJ, Meric-Bernstam F, Leitch AM, Boughey JC, Unzeitig G, Buzdar AU, Hunt KK, Mardis ER. Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial. Ann Oncol. 2017 May 1;28(5):1070-1077. doi: 10.1093/annonc/mdx048.
    pmid
    28453704
    type
    DERIVED
  3. citation
    Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group investigators. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. doi: 10.1016/S1470-2045(13)70502-3. Epub 2013 Nov 13.
    pmid
    24239210
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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      source update dates
      1. context
        Updated: April 25, 2025
        datetime
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        display
        April 25, 2025

    Preserved source evidence · Not medical advice