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

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

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.

Study Overview

• Status: Completed
• Conditions: Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; HER2/Neu Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Trastuzumab; Drug: Paclitaxel; Drug: Cyclophosphamide; Procedure: Therapeutic Conventional Surgery; Drug: Epirubicin Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 280
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936
    • San Juan City Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36688
      • University of South Alabama Mitchell Cancer Institute
  • California
    • Castro Valley, California, United States, 94546
      • Eden Hospital Medical Center
    • Greenbrae, California, United States, 94904
      • Marin Cancer Care Inc
    • Hayward, California, United States, 94545
      • Saint Rose Hospital
    • Pleasanton, California, United States, 94588
      • Valley Care Health System - Pleasanton
    • Pleasanton, California, United States, 94588
      • Valley Medical Oncology Consultants
  • Florida
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital
    • Fort Lauderdale, Florida, United States, 33316
      • Broward Health Medical Center
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Cancer Center
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60631
      • Presence Resurrection Medical Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Saint Francis Hospital and Health Centers
    • Indianapolis, Indiana, United States, 46237
      • Franciscan Saint Francis Health-Indianapolis
    • Richmond, Indiana, United States, 47374
      • Reid Hospital and Health Care Services
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
    • Sioux City, Iowa, United States, 51104
      • Saint Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center-Sioux City
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas - El Dorado
    • Fort Scott, Kansas, United States, 66701
      • Cancer Center of Kansas - Fort Scott
    • Independence, Kansas, United States, 67301
      • Cancer Center of Kansas-Independence
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas-Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Liberal, Kansas, United States, 67901
      • Cancer Center of Kansas-Liberal
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas - Newton
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas - Pratt
    • Salina, Kansas, United States, 67401
      • Cancer Center of Kansas - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas - Wellington
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas-Wichita Medical Arts Tower
    • Wichita, Kansas, United States, 67208
      • Associates In Womens Health
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Main Office
    • Wichita, Kansas, United States, 67214
      • Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
    • Wichita, Kansas, United States, 67214
      • Wichita CCOP
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas - Winfield
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
    • Louisville, Kentucky, United States, 40202
      • The James Graham Brown Cancer Center at University of Louisville
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Unspecified Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Cancer Center
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Saint Mary's Medical Center
    • Duluth, Minnesota, United States, 55805
      • Miller-Dwan Hospital
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Pascagoula, Mississippi, United States, 39581
      • Singing River Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Hospital and Medical Center
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
  • New Hampshire
    • Portsmouth, New Hampshire, United States, 03802
      • Portsmouth Regional Hospital
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Newark, New Jersey, United States, 07103
      • UMDNJ - New Jersey Medical School
    • Paterson, New Jersey, United States, 07503
      • Saint Joseph's Regional Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
    • Albuquerque, New Mexico, United States, 87110
      • Presbyterian Kaseman Hospital
  • New York
    • Middletown, New York, United States, 10940
      • Orange Regional Medical Center
    • Poughkeepsie, New York, United States, 12601
      • MidHudson Regional Hospital of Westchester Medical Center
    • Staten Island, New York, United States, 10305
      • Staten Island University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28816
      • Hope Women's Cancer Centers-Asheville
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
  • Ohio
    • Bellefontaine, Ohio, United States, 43311
      • Mary Rutan Hospital
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health Center West
    • Columbus, Ohio, United States, 43215
      • Columbus CCOP
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital - Dayton
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Health Center
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45420
      • Dayton CCOP
    • Dayton, Ohio, United States, 45428
      • Veteran Affairs Medical Center
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Hospital
    • Franklin, Ohio, United States, 45005-1066
      • Atrium Medical Center-Middletown Regional Hospital
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Marietta, Ohio, United States, 45750
      • Marietta Memorial Hospital
    • Mount Vernon, Ohio, United States, 43050
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Hospital
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center
    • Springfield, Ohio, United States, 45505
      • Springfield Regional Medical Center
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Center
    • Westerville, Ohio, United States, 43081
      • Saint Ann's Hospital
    • Wilmington, Ohio, United States, 45177
      • Clinton Memorial Hospital
    • Xenia, Ohio, United States, 45385
      • Greene Memorial Hospital
    • Zanesville, Ohio, United States, 43701
      • Genesis Healthcare System
  • Oklahoma
    • Lawton, Oklahoma, United States, 73505
      • Cancer Centers of Southwest Oklahoma Research
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • Saint Luke's University Hospital-Bethlehem Campus
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee - Knoxville
    • Nashville, Tennessee, United States, 37208
      • Meharry Medical College
    • Nashville, Tennessee, United States, 37203
      • Nashville Breast Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • The Don and Sybil Harrington Cancer Center
    • Dallas, Texas, United States, 75235
      • Parkland Memorial Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Dallas, Texas, United States, 75390
      • Clements University Hospital
    • Dallas, Texas, United States, 75235
      • Zale Lipshy University Hospital
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Laredo, Texas, United States, 78041
      • Doctor's Hospital of Laredo
    • Lubbock, Texas, United States, 79410
      • Covenant Medical Center-Lakeside
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
    • Newport News, Virginia, United States, 23606
      • Sentara Port Warwick
  • Washington
    • Seattle, Washington, United States, 98122-4307
      • Swedish Medical Center-First Hill
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Medical Center
    • Oconomowoc, Wisconsin, United States, 53066-3896
      • Oconomowoc Memorial Hospital-ProHealth Care Inc
    • Waukesha, Wisconsin, United States, 53188
      • Waukesha Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FEC-75 then Paclitaxel/trastuzumab; 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Trastuzumab; Given IV; Other Names: Herceptin; ABP 980; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; PF-05280014; rhuMAb HER2; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar PF-05280014; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Procedure: Therapeutic Conventional Surgery; Undergo surgery; Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence; IMI-28; Pharmorubicin PFS
Experimental: Paclitaxel/trastuzumab then trastuzumab/FEC-75; 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Trastuzumab; Given IV; Other Names: Herceptin; ABP 980; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; c-erb-2 Monoclonal Antibody; HER2 Monoclonal Antibody; Herceptin Biosimilar PF-05280014; Herceptin Trastuzumab Biosimilar PF-05280014; MoAb HER2; Monoclonal Antibody c-erb-2; Monoclonal Antibody HER2; PF-05280014; rhuMAb HER2; Trastuzumab Biosimilar ABP 980; Trastuzumab Biosimilar PF-05280014; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Procedure: Therapeutic Conventional Surgery; Undergo surgery; Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence; IMI-28; Pharmorubicin PFS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy	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.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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).	Up to 5 years
Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12	The summary of asymptomatic decrease in LVEF.	Baseline, at 12 week
Asymptomatic Decreases From Baseline in LVEF at Week 24	The summary of asymptomatic changed in LVEF.	Baseline, at 24 week
LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week	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)].	At 12 week
Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week	Difference from pretreatment LVEF (%) at 24 weeks [median change from baseline Inter Quartile Range (IQR)].	Baseline, at 24 week
Breast Conservation	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).	From time surgery to up to 5 years
Disease-free Survival (DFS)	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.	From time to registration to time of event, assessed up to 5 years
Overall Survival (OS)	OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.	From time to registration to death, assessed up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Aman Buzdar, American College of Surgeons

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): February 21, 2013

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 3, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Trastuzumab; Antibodies; Epirubicin; Immunoglobulins; Albumin-Bound Paclitaxel; Antibodies, Monoclonal; Antineoplastic Agents, Immunological
• Other Study ID Numbers: NCI-2009-00341 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA012027 (U.S. NIH Grant/Contract); CDR0000559039; ACOSOG-Z1041 (Other Identifier: CTEP); Z1041 (Other Identifier: American College of Surgeons Oncology Group)