Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	18 and over	NCI	ACOSOG-Z1041 Z1041, NCT00513292

Special Category: CTSU trial

Objectives

Primary

1. To compare the pathologic complete response rate (pCR) within the breast of patients with breast cancer receiving neoadjuvant combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, and cyclophosphamide followed by paclitaxel and trastuzumab vs neoadjuvant paclitaxel with trastuzumab (Herceptin®) followed by combination chemotherapy comprising fluoroucacil, epirubicin hydrochloride, cyclophosphamide, and trastuzumab.

Secondary

1. To estimate and compare the cardiotoxicity in patients receiving these regimens.
2. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study.
3. To compare the clinical response rates of the two regimens evaluated in this study.
4. To compare the non-cardiac toxicity of the two regimens evaluated in this study.
5. To compare breast conservation rates achieved with the two regimens evaluated in this study.
6. To evaluate disease-free survival and overall survival at 5 years post-randomization.
7. To correlate pCR rate with potential molecular markers of response.

Entry Criteria

Disease Characteristics:

• 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 prior history of invasive breast cancer
• Hormone receptor status known

Prior/Concurrent Therapy:

• 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

Patient Characteristics:

• 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
• LVEF ≥ 55 by MUGA or 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

Expected Enrollment

Outcomes

Pathologic complete response within the breast

Combined pathologic complete response rate in the breast and axillary lymph nodes
Cardiac event rate during treatment and follow-up
LVEF by MUGA or ECHO at baseline and 3 and 6 months
Method of definitive surgery
Adverse events by CTCAE version 3.0
Disease-free and overall survival at 5 years

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 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 2 years and then every 6 months for 3 years.

Trial Contact Information

Trial Lead Organizations

American College of Surgeons Oncology Group

Aman Buzdar, MD, Protocol chair		Ph: 713-792-2817; 800-392-1611
Kelly Hunt, MD, Protocol co-chair		Ph: 713-792-7216; 800-392-1611 Email: khunt@mdanderson.org

U.S.A.
Alabama
	Mobile
	University of South Alabama Mitchell Cancer Institute
		Donna Dyess	Ph:  251-460-6993
California
	Castro Valley
	East Bay Radiation Oncology Center
		James Feusner, MD	Ph:  510-428-3689
	Eden Medical Center
		James Feusner, MD	Ph:  510-428-3689
	Valley Medical Oncology Consultants - Castro Valley
		James Feusner, MD	Ph:  510-428-3689
	Fremont
	Valley Medical Oncology
		James Feusner, MD	Ph:  510-428-3689
	Martinez
	Contra Costa Regional Medical Center
		James Feusner, MD	Ph:  510-428-3689
	Mountain View
	El Camino Hospital Cancer Center
		Clinical Trials Office - El Camino Hospital Cancer Center	Ph:  650-988-7623
	Oakland
	Alta Bates Summit Medical Center - Summit Campus
		Clinical Trials Office - Alta Bates Summit Medical Center - Summit Campus	Ph:  510-204-1414
	Bay Area Breast Surgeons, Incorporated
		James Feusner, MD	Ph:  510-428-3689
	CCOP - Bay Area Tumor Institute
		James Feusner, MD	Ph:  510-428-3689
	Highland General Hospital
		James Feusner, MD	Ph:  510-428-3689
	Larry G Strieff MD Medical Corporation
		James Feusner, MD	Ph:  510-428-3689
	Tom K Lee, Incorporated
		James Feusner, MD	Ph:  510-428-3689
	Pleasanton
	Valley Care Medical Center
		James Feusner, MD	Ph:  510-428-3689
	Valley Medical Oncology Consultants - Pleasanton
		James Feusner, MD	Ph:  510-428-3689
	San Pablo
	Doctors Medical Center - San Pablo Campus
		James Feusner, MD	Ph:  510-428-3689
Florida
	Clearwater
	Morton Plant Hospital
		Peter Blumencranz, MD	Ph:  727-462-2131
	Lakeland
	Lakeland Regional Cancer Center at Lakeland Regional Medical Center
		Madhavi Venigalla, MD	Ph:  508-368-3168
Georgia
	Gainesville
	Northeast Georgia Medical Center
		Pierce Dixon, MD	Ph:  770-531-0093
Illinois
	Chicago
	Resurrection Medical Center
		Christopher Rose, MD	Ph:  847-965-3200
	Evanston
	Evanston Hospital
		Clinical Trials Office - Evanston Hospital	Ph:  847-570-1381
Indiana
	Beech Grove
	St. Francis Hospital and Health Centers - Beech Grove Campus
		Daniel McKellar, MD	Ph:  937-832-9310
	Richmond
	Reid Hospital & Health Care Services
		Daniel McKellar, MD	Ph:  937-832-9310
Iowa
	Sioux City
	Mercy Medical Center - Sioux City
		Donald Wender, MD, PhD	Ph:  712-252-0088
	Siouxland Hematology-Oncology Associates, LLP
		Donald Wender, MD, PhD	Ph:  712-252-0088
	St. Luke's Regional Medical Center
		Donald Wender, MD, PhD	Ph:  712-252-0088
Kansas
	Chanute
	Cancer Center of Kansas, PA - Chanute
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Dodge City
	Cancer Center of Kansas, PA - Dodge City
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	El Dorado
	Cancer Center of Kansas, PA - El Dorado
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Fort Scott
	Cancer Center of Kansas - Fort Scott
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Independence
	Cancer Center of Kansas-Independence
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Kingman
	Cancer Center of Kansas, PA - Kingman
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Lawrence
	Lawrence Memorial Hospital
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Liberal
	Southwest Medical Center
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Newton
	Cancer Center of Kansas, PA - Newton
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Parsons
	Cancer Center of Kansas, PA - Parsons
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Pratt
	Cancer Center of Kansas, PA - Pratt
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Salina
	Cancer Center of Kansas, PA - Salina
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Wellington
	Cancer Center of Kansas, PA - Wellington
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Wichita
	Associates in Womens Health, PA - North Review
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Cancer Center of Kansas, PA - Wichita
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Cancer Center of Kansas, PA - Medical Arts Tower
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	CCOP - Wichita
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Via Christi Cancer Center at Via Christi Regional Medical Center
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
	Winfield
	Cancer Center of Kansas, PA - Winfield
		Shaker Dakhil, MD, FACP	Ph:  316-262-4467
Kentucky
	Lexington
	Central Baptist Hospital
		Clinical Trials Office - Central Baptist Hospital	Ph:  859-260-6425
	Louisville
	James Graham Brown Cancer Center at University of Louisville
		Dharamvir Jain	Ph:  502-562-4158 866-530-5516
Minnesota
	Duluth
	CCOP - Duluth
		Daniel Nikcevich, MD, PhD	Ph:  218-786-3625
	Duluth Clinic Cancer Center - Duluth
		Clinical Trials Office - Duluth Clinic Cancer Center - Duluth	Ph:  218-786-3308
	Miller - Dwan Medical Center
		Daniel Nikcevich, MD, PhD	Ph:  218-786-3625
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Mississippi
	Pascagoula
	Regional Cancer Center at Singing River Hospital
		James Clarkson, MD	Ph:  228-374-6296
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Matthew Ellis, MD, PhD, FRCP	Ph:  314-747-7502
New Mexico
	Albuquerque
	Presbyterian Cancer Treatment Center at Presbyterian Kaseman Hospital
		Anne Wallace, MD	Ph:  858-822-6193
	University of New Mexico Cancer Center
		Clinical Trials Office - University of New Mexico Cancer Center	Ph:  505-272-6972
North Carolina
	Asheville
	Hope A Women's Cancer Center
		David Hetzel, MD	Ph:  828-670-8403
	Goldsboro
	Wayne Memorial Hospital, Incorporated
		James Atkins, MD	Ph:  919-580-0000
Ohio
	Bellefontaine
	Mary Rutan Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Chillicothe
	Adena Regional Medical Center
		Clinical Trials Office - Adena Regional Medical Center	Ph:  877-779-7585
	Columbus
	CCOP - Columbus
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Doctors Hospital at Ohio Health
		Clinical Trials Office - Doctors Hospital at Ohio Health	Ph:  614-566-3275
	Grant Medical Center Cancer Care
		Clinical Trials Office - Grant Medical Center Cancer Care	Ph:  614-566-4475
	Mount Carmel Health - West Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Riverside Methodist Hospital Cancer Care
		Clinical Trials Office - Riverside Methodist Hospital Cancer Care	Ph:  614-566-4475
	Dayton
	CCOP - Dayton
		Daniel McKellar, MD	Ph:  937-832-9310
	David L. Rike Cancer Center at Miami Valley Hospital
		Clinical Trials Office - David L. Rike Cancer Center at Miami Valley Hospital	Ph:  937-208-2079
	Good Samaritan Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Grandview Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Samaritan North Cancer Care Center
		Daniel McKellar, MD	Ph:  937-832-9310
	Delaware
	Grady Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Findlay
	Blanchard Valley Medical Associates
		Daniel McKellar, MD	Ph:  937-832-9310
	Franklin
	Middletown Regional Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Greenville
	Wayne Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Kettering
	Charles F. Kettering Memorial Hospital
		Clinical Trials Office - Charles F. Kettering Memorial Hospital	Ph:  937-298-3399 ext. 57556
	Lancaster
	Fairfield Medical Center
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Marietta
	Strecker Cancer Center at Marietta Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Newark
	Licking Memorial Cancer Care Program at Licking Memorial Hospital
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Springfield
	Community Hospital of Springfield and Clark County
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Mercy Medical Center
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Troy
	UVMC Cancer Care Center at Upper Valley Medical Center
		Clinical Trials Office - UVMC Cancer Care Center at Upper Valley Medical Center	Ph:  937-440-4842
	Westerville
	Mount Carmel St. Ann's Cancer Center
		J. Philip Kuebler, MD, PhD	Ph:  614-442-3130
	Wilmington
	Clinton Memorial Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Xenia
	Ruth G. McMillan Cancer Center at Greene Memorial Hospital
		Daniel McKellar, MD	Ph:  937-832-9310
	Zanesville
	Genesis - Good Samaritan Hospital
		Clinical Trials Office - Genesis - Good Samaritan Hospital	Ph:  740-454-5232
Oklahoma
	Lawton
	Cleo Craig Cancer Research Clinic
		Nadim Nimeh, MD	Ph:  580-536-2121ext.113
Pennsylvania
	Bethlehem
	St. Luke's Cancer Network at St. Luke's Hospital
		Darius Desai, MD	Ph:  610-954-2140
South Carolina
	Charleston
	Hollings Cancer Center at Medical University of South Carolina
		Clinical Trials Office - Hollings Cancer Center at Medical University of South Carolina	Ph:  843-792-9321
Tennessee
	Knoxville
	U.T. Medical Center Cancer Institute
		Clinical Trials Office - U.T. Medical Center Cancer Institute	Ph:  865-544-9773
Texas
	Amarillo
	Harrington Cancer Center
		Clinical Trials Officec - Harrington Cancer Center	Ph:  806-359-4673
			Email: ryokubaitis@harringtoncc.org
	Dallas
	Parkland Memorial Hospital
		Ann Leitch, MD	Ph:  214-648-3039
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		Clinical Trials Office - Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Ph:  866-460-4673; 214-648-7097
	UT Southwestern University Hospital - Zale Lipshy
		Ann Leitch, MD	Ph:  214-648-3039
	Houston
	M. D. Anderson Cancer Center at University of Texas
		Clinical Trials Office - M. D. Anderson Cancer Center at the University of Texas	Ph:  713-792-3245
	Laredo
	Doctor's Hospital of Laredo
		Gary Unzeitig, MD	Ph:  956-726-3691
Virginia
	Danville
	Danville Regional Medical Center
		Clinical Trials Office - Danville Regional Medical Center	Ph:  434-799-3753
	Newport News
	Surgical Oncology Associates
		Richard Hoefer, Jr.	Ph:  757-594-6770
Washington
	Seattle
	Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
		J. David Beatty, MD	Ph:  206-215-6400
Wisconsin
	La Crosse
	Gundersen Lutheran Center for Cancer and Blood
		Clinical Trials Office - Gundersen Lutheran Cancer Center	Ph:  608-775-2385
			Email: cancerctr@gundluth.org
	Oconomowoc
	Regional Cancer Center at Oconomowoc Memorial Hospital
		Clinical Trials Office - Regional Cancer Center at Oconomowoc Memorial Hospital	Ph:  262-928-7878
	Waukesha
	Waukesha Memorial Hospital Regional Cancer Center
		Clinical Trials Office - Waukesha Memorial Hospital Regional Cancer Center	Ph:  262-928-7632

Registry Information
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
Trial Start Date		2007-07-02
Trial Completion Date		2008-06-01 (estimated)
Registered in ClinicalTrials.gov		NCT00513292
Date Submitted to PDQ		2007-07-02
Information Last Verified		2009-11-15
NCI Grant/Contract Number		CA12027

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