Clinical trial NCT00513292: Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HER2/Neu Positive
Stage IA Breast Cancer
Stage IB Breast Cancer
Stage II Breast Cancer
Stage IIIA Breast Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-08-08
Enrollment: 280
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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

Primary outcomes:
measure: pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy
timeFrame: Up to 5 years
Secondary outcomes:
measure: 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
timeFrame: Up to 5 years
measure: Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12
timeFrame: Baseline, at 12 week
measure: Asymptomatic Decreases From Baseline in LVEF at Week 24
timeFrame: Baseline, at 24 week
measure: LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week
timeFrame: At 12 week
measure: Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week
timeFrame: Baseline, at 24 week
measure: Breast Conservation
timeFrame: From time surgery to up to 5 years
measure: Disease-free Survival (DFS)
timeFrame: From time to registration to time of event, assessed up to 5 years
measure: Overall Survival (OS)
timeFrame: From time to registration to death, assessed up to 5 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama Mitchell Cancer Institute
state: Alabama
city: Castro Valley
country: United States
facility: Eden Hospital Medical Center
state: California
city: Greenbrae
country: United States
facility: Marin Cancer Care Inc
state: California
city: Hayward
country: United States
facility: Saint Rose Hospital
state: California
city: Pleasanton
country: United States
facility: Valley Care Health System - Pleasanton
state: California
city: Pleasanton
country: United States
facility: Valley Medical Oncology Consultants
state: California
city: Clearwater
country: United States
facility: Morton Plant Hospital
state: Florida
city: Fort Lauderdale
country: United States
facility: Broward Health Medical Center
state: Florida
city: Lakeland
country: United States
facility: Lakeland Regional Cancer Center
state: Florida
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Chicago
country: United States
facility: Presence Resurrection Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: Saint Francis Hospital and Health Centers
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Saint Francis Health-Indianapolis
state: Indiana
city: Richmond
country: United States
facility: Reid Hospital and Health Care Services
state: Indiana
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Sioux City
country: United States
facility: Mercy Medical Center-Sioux City
state: Iowa
city: Sioux City
country: United States
facility: Saint Luke's Regional Medical Center
state: Iowa
city: Chanute
country: United States
facility: Cancer Center of Kansas - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas - Dodge City
state: Kansas
city: El Dorado
country: United States
facility: Cancer Center of Kansas - El Dorado
state: Kansas
city: Fort Scott
country: United States
facility: Cancer Center of Kansas - Fort Scott
state: Kansas
city: Independence
country: United States
facility: Cancer Center of Kansas-Independence
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas-Kingman
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Liberal
country: United States
facility: Cancer Center of Kansas-Liberal
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas - Newton
state: Kansas
city: Parsons
country: United States
facility: Cancer Center of Kansas - Parsons
state: Kansas
city: Pratt
country: United States
facility: Cancer Center of Kansas - Pratt
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas - Salina
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates In Womens Health
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas-Wichita Medical Arts Tower
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas - Main Office
state: Kansas
city: Wichita
country: United States
facility: Via Christi Regional Medical Center
state: Kansas
city: Wichita
country: United States
facility: Wesley Medical Center
state: Kansas
city: Wichita
country: United States
facility: Wichita CCOP
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas - Winfield
state: Kansas
city: Lexington
country: United States
facility: Baptist Health Lexington
state: Kentucky
city: Louisville
country: United States
facility: The James Graham Brown Cancer Center at University of Louisville
state: Kentucky
city: Rockville
country: United States
facility: Unspecified Site
state: Maryland
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Duluth
country: United States
facility: Essentia Health Cancer Center
state: Minnesota
city: Duluth
country: United States
facility: Essentia Health Saint Mary's Medical Center
state: Minnesota
city: Duluth
country: United States
facility: Miller-Dwan Hospital
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Pascagoula
country: United States
facility: Singing River Hospital
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation CCOP
state: Nevada
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Portsmouth
country: United States
facility: Portsmouth Regional Hospital
state: New Hampshire
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Newark
country: United States
facility: UMDNJ - New Jersey Medical School
state: New Jersey
city: Paterson
country: United States
facility: Saint Joseph's Regional Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Albuquerque
country: United States
facility: Presbyterian Kaseman Hospital
state: New Mexico
city: Middletown
country: United States
facility: Orange Regional Medical Center
state: New York
city: Poughkeepsie
country: United States
facility: MidHudson Regional Hospital of Westchester Medical Center
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital
state: New York
city: Asheville
country: United States
facility: Hope Women's Cancer Centers-Asheville
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Bellefontaine
country: United States
facility: Mary Rutan Hospital
state: Ohio
city: Canton
country: United States
facility: Aultman Health Foundation
state: Ohio
city: Chillicothe
country: United States
facility: Adena Regional Medical Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Columbus
country: United States
facility: Columbus CCOP
state: Ohio
city: Columbus
country: United States
facility: Grant Medical Center
state: Ohio
city: Columbus
country: United States
facility: Mount Carmel Health Center West
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital - Dayton
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Health Center
state: Ohio
city: Dayton
country: United States
facility: Dayton CCOP
state: Ohio
city: Dayton
country: United States
facility: Veteran Affairs Medical Center
state: Ohio
city: Delaware
country: United States
facility: Grady Memorial Hospital
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Hospital
state: Ohio
city: Franklin
country: United States
facility: Atrium Medical Center-Middletown Regional Hospital
state: Ohio
city: Greenville
country: United States
facility: Wayne Hospital
state: Ohio
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Lancaster
country: United States
facility: Fairfield Medical Center
state: Ohio
city: Marietta
country: United States
facility: Marietta Memorial Hospital
state: Ohio
city: Mount Vernon
country: United States
facility: Knox Community Hospital
state: Ohio
city: Newark
country: United States
facility: Licking Memorial Hospital
state: Ohio
city: Portsmouth
country: United States
facility: Southern Ohio Medical Center
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Medical Center
state: Ohio
city: Troy
country: United States
facility: Upper Valley Medical Center
state: Ohio
city: Westerville
country: United States
facility: Saint Ann's Hospital
state: Ohio
city: Wilmington
country: United States
facility: Clinton Memorial Hospital
state: Ohio
city: Xenia
country: United States
facility: Greene Memorial Hospital
state: Ohio
city: Zanesville
country: United States
facility: Genesis HealthCare System
state: Ohio
city: Lawton
country: United States
facility: Cancer Centers of Southwest Oklahoma Research
state: Oklahoma
city: Bethlehem
country: United States
facility: Saint Luke's University Hospital-Bethlehem Campus
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Knoxville
country: United States
facility: University of Tennessee - Knoxville
state: Tennessee
city: Nashville
country: United States
facility: Nashville Breast Center
state: Tennessee
city: Nashville
country: United States
facility: Meharry Medical College
state: Tennessee
city: Amarillo
country: United States
facility: The Don and Sybil Harrington Cancer Center
state: Texas
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Dallas
country: United States
facility: Zale Lipshy University Hospital
state: Texas
city: Dallas
country: United States
facility: Clements University Hospital
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Laredo
country: United States
facility: Doctor's Hospital of Laredo
state: Texas
city: Lubbock
country: United States
facility: Covenant Medical Center-Lakeside
state: Texas
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Newport News
country: United States
facility: Sentara Port Warwick
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: Oconomowoc Memorial Hospital-ProHealth Care Inc
state: Wisconsin
city: Waukesha
country: United States
facility: Waukesha Memorial Hospital
state: Wisconsin
city: San Juan
country: Puerto Rico
facility: San Juan City Hospital
Study officials:
affiliation: American College of Surgeons
name: Aman Buzdar
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.