Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery
NCT ID: NCT00513292
Last Updated: 2019-01-23
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
280 participants
INTERVENTIONAL
2007-07-31
2013-02-21
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
Cyclophosphamide
Given IV
Epirubicin Hydrochloride
Given IV
Laboratory Biomarker Analysis
Correlative studies
Paclitaxel
Given IV
Therapeutic Conventional Surgery
Undergo surgery
Trastuzumab
Given IV
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.
Cyclophosphamide
Given IV
Epirubicin Hydrochloride
Given IV
Laboratory Biomarker Analysis
Correlative studies
Paclitaxel
Given IV
Therapeutic Conventional Surgery
Undergo surgery
Trastuzumab
Given IV
Interventions
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Cyclophosphamide
Given IV
Epirubicin Hydrochloride
Given IV
Laboratory Biomarker Analysis
Correlative studies
Paclitaxel
Given IV
Therapeutic Conventional Surgery
Undergo surgery
Trastuzumab
Given IV
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
18 Years
FEMALE
No
Sponsors
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National Cancer Institute (NCI)
NIH
Responsible Party
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Principal Investigators
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Aman Buzdar
Role: PRINCIPAL_INVESTIGATOR
American College of Surgeons
Locations
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University of South Alabama Mitchell Cancer Institute
Mobile, Alabama, United States
Eden Hospital Medical Center
Castro Valley, California, United States
Marin Cancer Care Inc
Greenbrae, California, United States
Saint Rose Hospital
Hayward, California, United States
Valley Care Health System - Pleasanton
Pleasanton, California, United States
Valley Medical Oncology Consultants
Pleasanton, California, United States
Morton Plant Hospital
Clearwater, Florida, United States
Broward Health Medical Center
Fort Lauderdale, Florida, United States
Lakeland Regional Cancer Center
Lakeland, Florida, United States
Northeast Georgia Medical Center
Gainesville, Georgia, United States
Presence Resurrection Medical Center
Chicago, Illinois, United States
Saint Francis Hospital and Health Centers
Beech Grove, Indiana, United States
Franciscan Saint Francis Health-Indianapolis
Indianapolis, Indiana, United States
Reid Hospital and Health Care Services
Richmond, Indiana, United States
Siouxland Regional Cancer Center
Sioux City, Iowa, United States
Mercy Medical Center-Sioux City
Sioux City, Iowa, United States
Saint Luke's Regional Medical Center
Sioux City, Iowa, United States
Cancer Center of Kansas - Chanute
Chanute, Kansas, United States
Cancer Center of Kansas - Dodge City
Dodge City, Kansas, United States
Cancer Center of Kansas - El Dorado
El Dorado, Kansas, United States
Cancer Center of Kansas - Fort Scott
Fort Scott, Kansas, United States
Cancer Center of Kansas-Independence
Independence, Kansas, United States
Cancer Center of Kansas-Kingman
Kingman, Kansas, United States
Lawrence Memorial Hospital
Lawrence, Kansas, United States
Cancer Center of Kansas-Liberal
Liberal, Kansas, United States
Cancer Center of Kansas - Newton
Newton, Kansas, United States
Cancer Center of Kansas - Parsons
Parsons, Kansas, United States
Cancer Center of Kansas - Pratt
Pratt, Kansas, United States
Cancer Center of Kansas - Salina
Salina, Kansas, United States
Cancer Center of Kansas - Wellington
Wellington, Kansas, United States
Associates In Womens Health
Wichita, Kansas, United States
Cancer Center of Kansas-Wichita Medical Arts Tower
Wichita, Kansas, United States
Cancer Center of Kansas - Main Office
Wichita, Kansas, United States
Via Christi Regional Medical Center
Wichita, Kansas, United States
Wesley Medical Center
Wichita, Kansas, United States
Wichita CCOP
Wichita, Kansas, United States
Cancer Center of Kansas - Winfield
Winfield, Kansas, United States
Baptist Health Lexington
Lexington, Kentucky, United States
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, United States
Unspecified Site
Rockville, Maryland, United States
Borgess Medical Center
Kalamazoo, Michigan, United States
Bronson Methodist Hospital
Kalamazoo, Michigan, United States
West Michigan Cancer Center
Kalamazoo, Michigan, United States
Essentia Health Cancer Center
Duluth, Minnesota, United States
Essentia Health Saint Mary's Medical Center
Duluth, Minnesota, United States
Miller-Dwan Hospital
Duluth, Minnesota, United States
Mayo Clinic
Rochester, Minnesota, United States
Singing River Hospital
Pascagoula, Mississippi, United States
Washington University School of Medicine
St Louis, Missouri, United States
Nevada Cancer Research Foundation CCOP
Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
Las Vegas, Nevada, United States
Portsmouth Regional Hospital
Portsmouth, New Hampshire, United States
Saint Barnabas Medical Center
Livingston, New Jersey, United States
UMDNJ - New Jersey Medical School
Newark, New Jersey, United States
Saint Joseph's Regional Medical Center
Paterson, New Jersey, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States
University of New Mexico
Albuquerque, New Mexico, United States
Presbyterian Kaseman Hospital
Albuquerque, New Mexico, United States
Orange Regional Medical Center
Middletown, New York, United States
MidHudson Regional Hospital of Westchester Medical Center
Poughkeepsie, New York, United States
Staten Island University Hospital
Staten Island, New York, United States
Hope Women's Cancer Centers-Asheville
Asheville, North Carolina, United States
Wayne Memorial Hospital
Goldsboro, North Carolina, United States
Mary Rutan Hospital
Bellefontaine, Ohio, United States
Aultman Health Foundation
Canton, Ohio, United States
Adena Regional Medical Center
Chillicothe, Ohio, United States
Riverside Methodist Hospital
Columbus, Ohio, United States
Columbus CCOP
Columbus, Ohio, United States
Grant Medical Center
Columbus, Ohio, United States
Mount Carmel Health Center West
Columbus, Ohio, United States
Doctors Hospital
Columbus, Ohio, United States
Grandview Hospital
Dayton, Ohio, United States
Good Samaritan Hospital - Dayton
Dayton, Ohio, United States
Miami Valley Hospital
Dayton, Ohio, United States
Samaritan North Health Center
Dayton, Ohio, United States
Dayton CCOP
Dayton, Ohio, United States
Veteran Affairs Medical Center
Dayton, Ohio, United States
Grady Memorial Hospital
Delaware, Ohio, United States
Blanchard Valley Hospital
Findlay, Ohio, United States
Atrium Medical Center-Middletown Regional Hospital
Franklin, Ohio, United States
Wayne Hospital
Greenville, Ohio, United States
Kettering Medical Center
Kettering, Ohio, United States
Fairfield Medical Center
Lancaster, Ohio, United States
Marietta Memorial Hospital
Marietta, Ohio, United States
Knox Community Hospital
Mount Vernon, Ohio, United States
Licking Memorial Hospital
Newark, Ohio, United States
Southern Ohio Medical Center
Portsmouth, Ohio, United States
Springfield Regional Medical Center
Springfield, Ohio, United States
Upper Valley Medical Center
Troy, Ohio, United States
Saint Ann's Hospital
Westerville, Ohio, United States
Clinton Memorial Hospital
Wilmington, Ohio, United States
Greene Memorial Hospital
Xenia, Ohio, United States
Genesis HealthCare System
Zanesville, Ohio, United States
Cancer Centers of Southwest Oklahoma Research
Lawton, Oklahoma, United States
Saint Luke's University Hospital-Bethlehem Campus
Bethlehem, Pennsylvania, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
University of Tennessee - Knoxville
Knoxville, Tennessee, United States
Nashville Breast Center
Nashville, Tennessee, United States
Meharry Medical College
Nashville, Tennessee, United States
The Don and Sybil Harrington Cancer Center
Amarillo, Texas, United States
Parkland Memorial Hospital
Dallas, Texas, United States
Zale Lipshy University Hospital
Dallas, Texas, United States
Clements University Hospital
Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, United States
M D Anderson Cancer Center
Houston, Texas, United States
Doctor's Hospital of Laredo
Laredo, Texas, United States
Covenant Medical Center-Lakeside
Lubbock, Texas, United States
Danville Regional Medical Center
Danville, Virginia, United States
Sentara Port Warwick
Newport News, Virginia, United States
Swedish Medical Center-First Hill
Seattle, Washington, United States
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, United States
Oconomowoc Memorial Hospital-ProHealth Care Inc
Oconomowoc, Wisconsin, United States
Waukesha Memorial Hospital
Waukesha, Wisconsin, United States
San Juan City Hospital
San Juan, , Puerto Rico
Countries
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References
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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.
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 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.
Other Identifiers
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NCI-2009-00341
Identifier Type: REGISTRY
Identifier Source: secondary_id
CDR0000559039
Identifier Type: -
Identifier Source: secondary_id
ACOSOG-Z1041
Identifier Type: -
Identifier Source: secondary_id
Z1041
Identifier Type: OTHER
Identifier Source: secondary_id
ACOSOG-Z1041
Identifier Type: OTHER
Identifier Source: secondary_id
NCI-2009-00341
Identifier Type: -
Identifier Source: org_study_id
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