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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00513292
First received: August 6, 2007
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
HER2-positive Breast Cancer
Stage IA Breast Cancer
Stage IB Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Drug: epirubicin hydrochloride
Drug: cyclophosphamide
Drug: paclitaxel
Biological: trastuzumab
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial Comparing a Neoadjuvant Regimen of FEC-75 Followed by Paclitaxel Plus Trastuzumab With a Neoadjuvant Regimen of Paclitaxel Plus Trastuzumab Followed by FEC-75 Plus Trastuzumab in Patients With HER-2 Positive Operable Breast Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    pCR rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review. pCR rates will be compared using the Mantel-Haenszel test, stratified by tumor size (2.0 - 4.0 cm, > 4.0 cm), age (< 50, >= 50) and hormone receptor status (ER- and PgR-negative, ER and/or PgR-positive). The test will be conducted at the two-sized 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Cardiac event rate in Arm II [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    A cardiac event is defined to be Class III/IV congestive heart failure (CHF) or definite/probable cardiac death, as defined in the protocol, and as adjudicated by the Cardiac Review Panel (CRP). A 95% confidence interval for this rate will be calculated using the "exact" fiducial binomial method. A cumulative incidence curve for the time to cardiac event will be constructed using the usual non-parametric estimator.

  • Proportion of patients experiencing a cardiac event on the two arms [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Compared using Fisher's exact test. The test will be conducted at the two-sized .05 level. A 95% confidence interval will be computed for the difference in cardiac event rates. Cumulative incidence curves for the time to cardiac event will be constructed using the usual non-parametric estimator.80. The ratio of crude hazards will be estimated by fitting a Cox model.

  • Follow-up of patients meeting criteria for cardiac events [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Follow-up of patients meeting criteria for cardiac events will be summarized in terms of vital status (alive at last follow-up, dead), symptoms, and cardiac medications (time free of cardiac medication). A similar summary will be made for all patients reporting symptoms of possible cardiac dysfunction that do not meet criteria for Class III/IV CHF, based on CRP. These two arms will also be compared to one another, and to the set of all patients who are required to discontinue trastuzumab due to asymptomatic declines in LVEF, using histograms of nadir and "most-current" LVEF.

  • LVEFs from regularly scheduled MUGA/Echo scans as reported [ Time Frame: At baseline, 3 and 6 months of registration ] [ Designated as safety issue: No ]
    Histograms will be constructed showing baseline, 3-month and 6-month LVEF for all patients by Arm. Comparisons to baseline will be made at each time point by the signed rank test. Comparison across randomized cohorts will be made by applying the rank sum test to pre-post differences in LVEF.

  • Cardiac risk factors [ Time Frame: Time from patient registration to cardiac event (Class III/IV CHF or definite/probable cardiac death), assessed up to 5 years ] [ Designated as safety issue: No ]
    Association of putative risk factors with trastuzumab-induced cardiac dysfunction will be tested using (univariate) log-rank analysis, stratified by treatment group. Risk factors include age at registration, baseline LVEF, history of hypertension, race/ethnicity, smoking history, left versus right sided breast cancers requiring radiation, family history of cardiac disease, and use of cardiovascular, diabetes or hyperlipidemia medications at baseline. Permutation method proposed by Peto and Peto will be used to compute p-values.

  • Adverse events (non-cardiac toxicity) as assessed by Common Terminology Criteria for Adverse Events version 3.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Adverse events will be tabulated by treatment arm, type, and greatest severity.

  • Beast conservation rates [ Time Frame: From time surgery to up to 5 years ] [ Designated as safety issue: No ]

    Method of definitive surgery, categorized as breast conserving surgery ("lumpectomy") or total mastectomy. Breast conservation rates will be compared using the Mantel-Haenszel test, stratified by tumor size (2.0 -4.0 cm, > 4.0 cm), age (< 50, >= 50) and hormone receptor status (ER- and PgR-negative, ER- and/or PgR positive).

    The test will be conducted at the two-sized .05 level. A 95% confidence interval will be computed for the difference in breast conservation rates.


  • Disease-free survival (DFS) [ Time Frame: From time to registration to time of event, assessed up to 5 years ] [ Designated as safety issue: No ]
    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. The difference will be tested using the log-rank test, stratified by tumor size (2.0 - 4.0 cm, > 4.0 cm), age (< 50, >= 50), and hormone receptor status (ER- and PgR-negative, ER- and/or PgR-positive).

  • Overall survival (OS) [ Time Frame: From time to registration to death, assessed up to 5 years ] [ Designated as safety issue: No ]
    OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method. The difference will be tested using the log-rank test, stratified by tumor size (2.0 - 4.0 cm, > 4.0 cm), age (< 50, >= 50), and hormone receptor status (ER- and PgR-negative, ER- and/or PgR-positive).


Estimated Enrollment: 270
Study Start Date: July 2007
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (chemotherapy and monoclonal antibody therapy)
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.
Drug: epirubicin hydrochloride
Given IV
Drug: cyclophosphamide
Given IV
Drug: paclitaxel
Given IV
Biological: trastuzumab
Given IV
Procedure: therapeutic conventional surgery
Undergo surgery
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm II (monoclonal antibody therapy, chemotherapy)
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.
Drug: epirubicin hydrochloride
Given IV
Drug: cyclophosphamide
Given IV
Drug: paclitaxel
Given IV
Biological: trastuzumab
Given IV
Procedure: therapeutic conventional surgery
Undergo surgery
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:

  • 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
  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: NCT00513292

  Show 112 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Aman Buzdar American College of Surgeons
  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: NCT00513292     History of Changes
Other Study ID Numbers: NCI-2009-00341, NCI-2009-00341, CDR0000559039, ACOSOG-Z1041, Z1041, ACOSOG-Z1041, U10CA012027
Study First Received: August 6, 2007
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies, Monoclonal
Cyclophosphamide
Trastuzumab
Epirubicin
Paclitaxel
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on August 28, 2014