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

Stage IIIA Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00513292
• Other study ID #: NCI-2009-00341
• Secondary ID: NCI-2009-00341CD
• Status: Completed
• Phase: Phase 3
• Start date: July 2007
• Est. completion date: February 21, 2013

Study information

• Verified date: January 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 280
• Est. completion date: February 21, 2013
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• HER2/Neu Positive
• Stage IA Breast Cancer
• Stage IB Breast Cancer
• Stage II Breast Cancer
• Stage IIIA Breast Cancer

Intervention

Drug:
• Cyclophosphamide
Given IV
• Epirubicin Hydrochloride
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Paclitaxel
Given IV

Procedure:
• Therapeutic Conventional Surgery
Undergo surgery

Biological:
• Trastuzumab
Given IV

Locations

Country	Name	City	State
Puerto Rico	San Juan City Hospital	San Juan
United States	Presbyterian Kaseman Hospital	Albuquerque	New Mexico
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	The Don and Sybil Harrington Cancer Center	Amarillo	Texas
United States	Hope Women's Cancer Centers-Asheville	Asheville	North Carolina
United States	Saint Francis Hospital and Health Centers	Beech Grove	Indiana
United States	Mary Rutan Hospital	Bellefontaine	Ohio
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Aultman Health Foundation	Canton	Ohio
United States	Eden Hospital Medical Center	Castro Valley	California
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Presence Resurrection Medical Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Morton Plant Hospital	Clearwater	Florida
United States	Columbus CCOP	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Clements University Hospital	Dallas	Texas
United States	Parkland Memorial Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Zale Lipshy University Hospital	Dallas	Texas
United States	Danville Regional Medical Center	Danville	Virginia
United States	Dayton CCOP	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Veteran Affairs Medical Center	Dayton	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
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	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Marin Cancer Care Inc	Greenbrae	California
United States	Wayne Hospital	Greenville	Ohio
United States	Saint Rose Hospital	Hayward	California
United States	M D Anderson Cancer Center	Houston	Texas
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Franciscan Saint Francis Health-Indianapolis	Indianapolis	Indiana
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kettering Medical Center	Kettering	Ohio
United States	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	University of Tennessee - Knoxville	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Lakeland Regional Cancer Center	Lakeland	Florida
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Doctor's Hospital of Laredo	Laredo	Texas
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Cancer Center of Kansas-Liberal	Liberal	Kansas
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Orange Regional Medical Center	Middletown	New York
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Meharry Medical College	Nashville	Tennessee
United States	Nashville Breast Center	Nashville	Tennessee
United States	Licking Memorial Hospital	Newark	Ohio
United States	UMDNJ - New Jersey Medical School	Newark	New Jersey
United States	Sentara Port Warwick	Newport News	Virginia
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Singing River Hospital	Pascagoula	Mississippi
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Valley Care Health System - Pleasanton	Pleasanton	California
United States	Valley Medical Oncology Consultants	Pleasanton	California
United States	Portsmouth Regional Hospital	Portsmouth	New Hampshire
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	MidHudson Regional Hospital of Westchester Medical Center	Poughkeepsie	New York
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Reid Hospital and Health Care Services	Richmond	Indiana
United States	Mayo Clinic	Rochester	Minnesota
United States	Unspecified Site	Rockville	Maryland
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Staten Island University Hospital	Staten Island	New York
United States	Upper Valley Medical Center	Troy	Ohio
United States	Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Associates In Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas - Main Office	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	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	Clinton Memorial Hospital	Wilmington	Ohio
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Greene Memorial Hospital	Xenia	Ohio
United States	Genesis HealthCare System	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12	The summary of asymptomatic decrease in LVEF.	Baseline, at 12 week
Secondary	Asymptomatic Decreases From Baseline in LVEF at Week 24	The summary of asymptomatic changed in LVEF.	Baseline, at 24 week
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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