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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


Phase 3
18 Years
N/A
Open (Enrolling)
Female
HER2-positive Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

pCR within the breast, defined as no evidence of invasive tumor remaining in the breast at surgery following completion of chemotherapy

Outcome Description:

pCR rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review. pCR rates will be compared using the Mantel-Haenszel test, stratified by tumor size (2.0 - 4.0 cm, > 4.0 cm), age (< 50, >= 50) and hormone receptor status (ER- and PgR-negative, ER and/or PgR-positive). The test will be conducted at the two-sized 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates.

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

Aman Buzdar

Investigator Role:

Principal Investigator

Investigator Affiliation:

American College of Surgeons

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00341

NCT ID:

NCT00513292

Start Date:

July 2007

Completion Date:

Related Keywords:

  • HER2-positive Breast Cancer
  • Stage IA Breast Cancer
  • Stage IB Breast Cancer
  • Stage II Breast Cancer
  • Stage IIIA Breast Cancer
  • Breast Neoplasms

Name

Location

Mayo ClinicRochester, Minnesota  55905
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
Waukesha Memorial HospitalWaukesha, Wisconsin  53188
Staten Island University HospitalStaten Island, New York  10305
Broward General Medical CenterFort Lauderdale, Florida  33316
Via Christi Regional Medical CenterWichita, Kansas  67214
Central Baptist HospitalLexington, Kentucky  40503
Cancer Center of Kansas - ChanuteChanute, Kansas  66720
Cancer Center of Kansas - Dodge CityDodge City, Kansas  67801
Cancer Center of Kansas - NewtonNewton, Kansas  67114
Cancer Center of Kansas - SalinaSalina, Kansas  67042
Cancer Center of Kansas - WellingtonWellington, Kansas  67152
Associates in Womens HealthWichita, Kansas  67203
Cancer Center of Kansas - WinfieldWinfield, Kansas  67156
Adena Regional Medical CenterChillicothe, Ohio  54601
Grady Memorial HospitalDelaware, Ohio  43015
Fairfield Medical CenterLancaster, Ohio  43130
University of South Alabama Mitchell Cancer InstituteMobile, Alabama  36604
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Parkland Memorial HospitalDallas, Texas  75235
Saint Rose HospitalHayward, California  94545
Grandview HospitalDayton, Ohio  45405
Doctor's Hospital of LaredoLaredo, Texas  78041
Northeast Georgia Medical CenterGainesville, Georgia  30501
Miami Valley HospitalDayton, Ohio  45409
Cancer Center of Kansas - Fort ScottFort Scott, Kansas  66701
Cancer Center of Kansas-IndependenceIndependence, Kansas  67301
Lawrence Memorial HospitalLawrence, Kansas  66044
Mary Rutan HospitalBellefontaine, Ohio  43311
Wayne HospitalGreenville, Ohio  45331
Knox Community HospitalMount Vernon, Ohio  43050
Clinton Memorial HospitalWilmington, Ohio  45177
Morton Plant HospitalClearwater, Florida  33756
Singing River HospitalPascagoula, Mississippi  39581
Zale Lipshy University HospitalDallas, Texas  75235-7786
Greene Memorial HospitalXenia, Ohio  45385
Lakeland Regional Cancer CenterLakeland, Florida  33805
Riverside Methodist HospitalColumbus, Ohio  43214
Licking Memorial HospitalNewark, Ohio  43055-2899
Columbus CCOPColumbus, Ohio  43206
University of Texas Southwestern Medical CenterDallas, Texas  
Wichita CCOPWichita, Kansas  67214-3882
Thomas Jefferson University HospitalPhiladelphia, Pennsylvania  19131
M D Anderson Cancer CenterHouston, Texas  77030
Eden Hospital Medical CenterCastro Valley, California  94546
Valley Medical Oncology ConsultantsPleasanton, California  94588
Valley Care Health System - PleasantonPleasanton, California  94588
Resurrection HealthcareChicago, Illinois  60631
Saint Francis Hospital and Health CentersBeech Grove, Indiana  46107
Reid Hospital and Health Care ServicesRichmond, Indiana  47374
Mercy Medical Center-Sioux CitySioux City, Iowa  51104
Saint Luke's Regional Medical CenterSioux City, Iowa  51104
Cancer Center of Kansas - El DoradoEl Dorado, Kansas  67042
Cancer Center of Kansas-KingmanKingman, Kansas  67068
Cancer Center of Kansas - ParsonsParsons, Kansas  67357
Cancer Center of Kansas - PrattPratt, Kansas  67124
Cancer Center of Kansas-Wichita Medical Arts TowerWichita, Kansas  67208
Cancer Center of Kansas - Main OfficeWichita, Kansas  67214
Miller-Dwan HospitalDuluth, Minnesota  55805
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Portsmouth Regional HospitalPortsmouth, New Hampshire  03802
Presbyterian Kaseman HospitalAlbuquerque, New Mexico  87110
Orange Regional Medical CenterMiddletown, New York  10940
Doctors HospitalColumbus, Ohio  43228
Grant Medical CenterColumbus, Ohio  43215
Mount Carmel Health Center WestColumbus, Ohio  43222
Good Samaritan Hospital - DaytonDayton, Ohio  45406
Dayton CCOPDayton, Ohio  45429
Samaritan North Health CenterDayton, Ohio  45415
Veteran Affairs Medical CenterDayton, Ohio  45428
Blanchard Valley HospitalFindlay, Ohio  45840
Atrium Medical Center-Middletown Regional HospitalFranklin, Ohio  45005-1066
Kettering Medical CenterKettering, Ohio  45429
Marietta Memorial HospitalMarietta, Ohio  45750
Upper Valley Medical CenterTroy, Ohio  45373
Saint Ann's HospitalWesterville, Ohio  43081
Genesis HealthCare SystemZanesville, Ohio  43701
Saint Luke's HospitalBethlehem, Pennsylvania  18015
The Don and Sybil Harrington Cancer CenterAmarillo, Texas  79106
Swedish Medical Center-First HillSeattle, Washington  98122-4307
Oconomowoc Memorial Hospital-ProHealth Care IncOconomowoc, Wisconsin  53066-3896
Cancer Center of Kansas-LiberalLiberal, Kansas  67901
UMDNJ - New Jersey Medical SchoolNewark, New Jersey  07103
University of Tennessee - KnoxvilleKnoxville, Tennessee  37920
Saint Paul HospitalDallas, Texas  75235
Nashville Breast CenterNashville, Tennessee  37203
Hope, A Women's Cancer CenterAsheville, North Carolina  28816
Cancer Centers of Southwest Oklahoma ResearchLawton, Oklahoma  
Saint FrancisPoughkeepsie, New York  12601
Southern Ohio Medical CenterPortsmouth, Ohio  45662
Gundersen LutheranLa Crosse, Wisconsin  54601
Siouxland Hematology Oncology AssociatesSioux City, Iowa  51101
Essentia Health Duluth Clinic CCOPDuluth, Minnesota  55805
Essentia Health Saint Mary's Medical CenterDuluth, Minnesota  55805
Springfield Regional Medical CenterSpringfield, Ohio  45505
The James Graham Brown Cancer Center at University of LouisvilleLouisville, Kentucky  40202
Marin Cancer Care IncGreenbrae, California  94904
Covenant Medical Center-LakesideLubbock, Texas  79410