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A Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2


Phase 3
18 Years
N/A
Open (Enrolling)
Female
Breast Cancer

Thank you

Trial Information

A Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2


OBJECTIVES:

- Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel
with or without trastuzumab (Herceptin®) in women with operable, node-positive breast
cancer that overexpresses HER2.

- Compare the effect of these regimens on disease-free and overall survival of these
patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy
(tamoxifen vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast
irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy
without radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs
weekly), and participating center. Patients are randomized to one of two treatment arms.

- Arm 1: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day
1. Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last
course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR
paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).

- Arm 2: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over
90 minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered
IV over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal
therapy* for at least 5 years, beginning within 3-12 weeks after the last dose of
chemotherapy. Patients who have received prior tamoxifen for prevention may be treated with
additional tamoxifen for no more than 5 years at the discretion of the principal
investigator (PI).

NOTE: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative
to tamoxifen therapy.

All patients previously treated with lumpectomy undergo breast irradiation beginning after
completion of chemotherapy and concurrently with trastuzumab (in arm 2) administration.
Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is
administered daily for 5-6 weeks.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,700 patients will be accrued for this study within 4.75
years.

Inclusion Criteria


Inclusion criteria

- The patient must have a life expectancy of at least 10 years, excluding her diagnosis
of breast cancer. (Comorbid conditions should be taken into consideration, but not
the diagnosis of breast cancer.)

- The interval between the last surgery for breast cancer treatment (lumpectomy,
mastectomy, axillary dissection, or re-excision of lumpectomy margins) and
randomization must be less than or equal to 84 days.

- All of the following staging criteria must be met:

- Primary tumor must be T1-3 by clinical and pathologic evaluation.

- Ipsilateral nodes must be cN0-1 by clinical evaluation.

- Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.

- M0

- Patients must have undergone either a total mastectomy and an axillary dissection or
a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must
be followed by an axillary dissection.

- The tumor must be invasive adenocarcinoma on histologic examination.

- The tumor must be determined to be HER2-positive prior to randomization. Assays
performed using fluorescent in situ hybridization (FISH) require gene amplification
to be eligible. Assays using immunohistochemistry (IHC) must be performed at an
NSABP-approved reference laboratory and require a strongly positive staining score.

- Patients must have an analysis of both estrogen and progesterone receptors performed
on the primary tumor prior to randomization. "Marginal," "borderline," etc., results
(i.e., those not definitely negative) will also be considered positive regardless of
the methodology used.

- At the time of randomization, the patient must have had the following: history and
physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a
bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam
(for women who have a uterus and who will be taking tamoxifen) within the past year.

- Within 3 months prior to entry, the patient must have a baseline left ventricular
ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower
limit of normal for the radiology facility. (If LVEF is > 75%, the investigator
should consider having the LVEF determination reviewed prior to randomization.
Following randomization, the LVEF determination may be reviewed up until the time of
the post-AC MUGA. Please note that if a more accurate value is obtained from the
review of the baseline MUGA, the corrected value must be submitted to the NSABP
Biostatistical Center before the post-AC MUGA is performed.)

- At the time of randomization:

- The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or
<1500/mm3 if, in the opinion of the investigator, this represents an ethnic or
racial variation of normal).

- Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying
hematologic disorders must be excluded when the platelet count is above the
upper limit of normal for the lab.

- There must be postoperative evidence of adequate hepatic function, i.e., total
bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1
bilirubin elevation (>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar
syndrome; and alkaline phosphatase must be <2.5 times the ULN for the lab; and the
serum glutamic-oxaloacetic transaminase (SGOT [AST]) must be <1.5 times the ULN for
the lab.

- There must be postoperative evidence of adequate renal function (serum creatinine
within or less than the institution's normal range).

- Patients must have no clinical or radiologic evidence of metastatic disease.
Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy.
A patient with skeletal pain is eligible for inclusion in the study if bone scan
and/or roentgenological examination fails to disclose metastatic disease.

- Patients with a history of non-breast malignancies are eligible if they have been
disease-free for 5 or more years prior to randomization and are deemed by their
physician to be at low risk for recurrence. Patients with the following cancers are
eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the
cervix, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

- Prior to randomization, the investigator must designate whether the patients who had
a lumpectomy will receive local or locoregional radiation therapy. For patients who
had a mastectomy, the investigator must designate whether or not the patient will
receive radiation therapy. (Pre-randomization discussion and/or consultation with a
radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes
is prohibited in this trial.

- Special conditions for eligibility of lumpectomy patients: irradiation and surgery

- Patients treated by lumpectomy and axillary node dissection to be followed by breast
radiation therapy must meet all the eligibility criteria in addition to the
following: Generally, lumpectomy should be reserved for tumors <5 cm. However, at
the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are
eligible. The margins of the resected specimen must be histologically free of
invasive tumor and DCIS as determined by the local pathologist. In patients in whom
pathologic examination demonstrates tumor present at the line of resection,
additional operative procedures may be performed to obtain clear margins. This is
permissible even if axillary dissection has been performed. Patients in whom tumor
is still present at the resected margin after re-excision(s) must undergo total
mastectomy to be eligible. Whole breast irradiation is required. Irradiation of
regional lymph nodes is optional, but partial breast irradiation and irradiation of
any internal mammary nodes are prohibited in this trial. Intent to irradiate the
axilla or other regional node groups must be declared by the investigator prior to
randomization for stratification purposes.

- Special conditions for eligibility of mastectomy patients: irradiation. The decision
to use locoregional irradiation in patients who have undergone total mastectomy and
axillary node dissection must be declared by the investigator prior to randomization
for stratification purposes. Failure to adhere to the radiation therapy plan will be
a protocol violation.

Exclusion criteria

- Bilateral malignancy or a mass or mammographic abnormality in the opposite breast
suspicious for malignancy unless there is biopsy proof that the mass is not
malignant.

- Primary tumor staged as T4 for any reason.

- Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b,
pN3b, or pN3c.

- Prior history of breast cancer, including DCIS (patients with a history of lobular
carcinoma in situ [LCIS] are eligible).

- Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal
therapy administered for the currently diagnosed breast cancer prior to
randomization. The only exception is hormonal therapy, which may have been given for
up to a total of 28 days anytime after diagnosis and before randomization. In such a
case, hormonal therapy must stop at or before randomization and be re-started if
indicated following chemotherapy.

- Prior anthracycline or taxane therapy for any malignancy.

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement
therapy, etc. (These patients are eligible only if this therapy is discontinued
prior to randomization.)

- Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other
selective estrogen receptor modulators (SERMs), either for osteoporosis or
prevention. (Patients are eligible only if these medications are discontinued prior
to randomization. These medications are not permitted while on the study except for
the use of tamoxifen as described in the protocol)

- Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
preclude a patient from being subjected to any of the treatment options or would
prevent prolonged follow-up.

- Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This
includes:

- 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; or

- patients with poorly controlled hypertension, i.e., diastolic greater than 100
mm/Hg. (Patients with hypertension who are well controlled on medication are
eligible for entry.)

- History of cardiac disease:

- myocardial infarction documented as a clinical diagnosis or by EKG or any other
tests;

- documented congestive heart failure; or

- documented cardiomyopathy.

- Psychiatric or addictive disorders that would preclude obtaining informed consent.

- Pregnancy or lactation at the time of proposed randomization. This protocol excludes
pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol
which are listed as Pregnancy Category D agents. Pregnant women who received
tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and
vaginal bleeding. Women of reproductive potential must agree to use an effective
barrier method of contraception. Hormonal birth control methods are not permitted.

- Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria
version 2.0.

- Contraindications to corticosteroid use which, in the opinion of the investigator,
would preclude participation in this study.

- Concurrent treatment with other investigational agents.

- Sensitivity to benzyl alcohol.

- Special conditions for ineligibility of lumpectomy patients: irradiation and surgery.
For patients treated by lumpectomy with axillary dissection, breast irradiation is
required. Please see guidelines for radiation therapy in Appendix A. In addition,
the following patients will also be ineligible:

- Patients with diffuse tumors (as demonstrated on mammography) that would not be
considered surgically amenable to lumpectomy.

- Patients treated with lumpectomy in whom there is another clinically dominant
mass or mammographically suspicious abnormality within the ipsilateral breast
remnant. Such a mass must be biopsied and demonstrated to be histologically
benign prior to randomization or, if malignant, must be surgically removed with
clear margins.

- Patients in whom the margins of the resected specimen are involved with invasive
tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to
obtain free margins are allowed. Patients in whom tumor is still present after
the additional resection(s) must undergo mastectomy to be eligible.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Disease Free Survival (DFS)

Outcome Description:

Breast cancer recurrence, second primary cancer, death from any cause as first event

Outcome Time Frame:

Time from randomization through 5 years

Safety Issue:

No

Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.

Authority:

United States: Federal Government

Study ID:

NSABP B-31

NCT ID:

NCT00004067

Start Date:

February 2000

Completion Date:

March 2014

Related Keywords:

  • Breast Cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • Breast Neoplasms

Name

Location

Baylor College of Medicine Houston, Texas  77030
National Naval Medical Center Bethesda, Maryland  20889
CCOP - Upstate Carolina Spartanburg, South Carolina  29303
CCOP - Wichita Wichita, Kansas  67214-3882
Medical City Dallas Hospital Dallas, Texas  75230
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
CCOP - Atlanta Regional Atlanta, Georgia  30342-1701
CCOP - Kansas City Kansas City, Missouri  64131
CCOP - Missouri Valley Cancer Consortium Omaha, Nebraska  68131
CCOP - Southern Nevada Cancer Research Foundation Las Vegas, Nevada  89106
CCOP - Christiana Care Health Services Wilmington, Delaware  19899
CCOP - Mount Sinai Medical Center Miami Beach, Florida  33140
CCOP - Southeast Cancer Control Consortium Winston-Salem, North Carolina  27104-4241
MBCCOP - Massey Cancer Center Richmond, Virginia  23298-0037
CCOP - Illinois Oncology Research Association Peoria, Illinois  61602
CCOP - Carle Cancer Center Urbana, Illinois  61801
CCOP - Iowa Oncology Research Association Des Moines, Iowa  50309-1016
CCOP - Kalamazoo Kalamazoo, Michigan  49007-3731
CCOP - Metro-Minnesota Saint Louis Park, Minnesota  55416
CCOP - Northern New Jersey Hackensack, New Jersey  07601
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center Farmington, Connecticut  06360-2875
Methodist Cancer Center at Methodist Hospital Indianapolis, Indiana  46202
Baystate Regional Cancer Program at D'Amour Center for Cancer Care Springfield, Massachusetts  01199
CCOP - Michigan Cancer Research Consortium Ann Arbor, Michigan  48106
CCOP - Duluth Duluth, Minnesota  55805
Hennepin County Medical Center - Minneapolis Minneapolis, Minnesota  55415
Geisinger Medical Center Danville, Pennsylvania  17822-0001
Medical College of Wisconsin Cancer Center Milwaukee, Wisconsin  53226
CCOP - Ochsner New Orleans, Louisiana  70121
CCOP - Merit Care Hospital Fargo, North Dakota  58122
CCOP - Sioux Community Cancer Consortium Sioux Falls, South Dakota  57105-1080
Comprehensive Cancer Center at Wake Forest University Winston-Salem, North Carolina  27157-1082
Sutter Health Western Division Cancer Research Group Greenbrae, California  94904
CCOP - Bay Area Tumor Institute Oakland, California  94609-3305
CCOP - Santa Rosa Memorial Hospital Santa Rosa, California  95403
Halifax Medical Center Daytona Beach, Florida  32114
CCOP - Central Illinois Springfield, Illinois  62526
CCOP - Cancer Research for the Ozarks Springfield, Missouri  65807
CCOP - Montana Cancer Consortium Billings, Montana  59101
Newark Beth Israel Medical Center Newark, New Jersey  07112
CCOP - Columbus Columbus, Ohio  43206
CCOP - Dayton Kettering, Ohio  45429
Albert Einstein Cancer Center Philadelphia, Pennsylvania  19141
Mercy Hospital Cancer Center - Scranton Scranton, Pennsylvania  18501
CCOP - Greenville Greenville, South Carolina  29615
Joe Arrington Cancer Research and Treatment Center Lubbock, Texas  79410-1894
St. Vincent Hospital Green Bay, Wisconsin  54307-3508
CCOP - Western Regional, Arizona Phoenix, Arizona  85006-2726
University of Colorado Cancer Center at University of Colorado Health Sciences Center Denver, Colorado  80010
University of Miami Sylvester Comprehensive Cancer Center Miami, Florida  33136
CCOP - Evanston Evanston, Illinois  60201
CCOP - Northern Indiana CR Consortium South Bend, Indiana  46601
Holden Comprehensive Cancer Center at University of Iowa Iowa City, Iowa  52242-1002
UMASS Memorial Cancer Center - University Campus Worcester, Massachusetts  01605-2982
CCOP - Grand Rapids Grand Rapids, Michigan  49503
Ellis Fischel Cancer Center at University of Missouri - Columbia Columbia, Missouri  65203
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Chapel Hill, North Carolina  27599-7570
Charles M. Barrett Cancer Center at University Hospital Cincinnati, Ohio  45267-0526
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Columbus, Ohio  43210-1240
CCOP - Columbia River Oncology Program Portland, Oregon  97225
Kimmel Cancer Center at Thomas Jefferson University - Philadelphia Philadelphia, Pennsylvania  19107
CCOP - Scott and White Hospital Temple, Texas  76508
Cancer Research Center of Hawaii Honolulu, Hawaii  96813
Dwight David Eisenhower Army Medical Center Fort Gordon, Georgia  30905-5650
CCOP - St. Louis-Cape Girardeau Saint Louis, Missouri  63141
CCOP - Virginia Mason Research Center Seattle, Washington  98101
CCOP - Northwest Tacoma, Washington  98405-0986
Puget Sound Oncology Consortium Seattle, Washington  98109
Sutter Cancer Center Sacramento, California  95816
Kaiser Permanente Medical Center - Vallejo Vallejo, California  94589
West Suburban Hospital Medical Center Oak Park, Illinois  60302
Berkshire Medical Center Pittsfield, Massachusetts  01201
Michigan State University East Lansing, Michigan  48824
CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C. Syracuse, New York  13217
CCOP - Oklahoma Tulsa, Oklahoma  74136
Allegheny General Hospital Pittsburgh, Pennsylvania  15212-4772
Kent County Memorial Hospital Warwick, Rhode Island  02886
Utah Valley Regional Medical Center - Provo Provo, Utah  84604
Camden-Clark Memorial Hospital Parkersburg, West Virginia  26102
Providence Alaska Medical Center Anchorage, Alaska  99508
Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San Diego San Diego, California  92120
University of New Mexico Cancer Research and Treatment Center Albuquerque, New Mexico  87131
City of Hope Comprehensive Cancer Center Duarte, California  91010
CCOP - Colorado Cancer Research Program, Incorporated Denver, Colorado  80224
Hillman Cancer Center at University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15236
Markey Cancer Center at University of Kentucky Chandler Medical Center Lexington, Kentucky  40536-0084
Tulane Cancer Center at Tulane University Hospital and Clinic New Orleans, Louisiana  70112
Cancer Research Center at Boston Medical Center Boston, Massachusetts  02118
Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center Baltimore, Maryland  21237
Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University Cleveland, Ohio  44106
North Idaho Cancer Center Coeur d'Alene, Idaho  83814
Loma Linda University Cancer Institute at Loma Linda University Medical Center Loma Linda, California  92354
Winship Cancer Institute of Emory University Atlanta, Georgia  30322
CancerCare of Maine at Eastern Maine Medial Center Bangor, Maine  04401
Scripps Cancer Center at Scripps Clinic La Jolla, California  92037
Methodist Hospital Cancer Center at Nebraska Methodist Hospital - Omaha Omaha, Nebraska  68114-4199
Aultman Hospital Cancer Center at Aultman Health Foundation Canton, Ohio  44710-1799
CCOP - Marshfield Clinic Research Foundation Marshfield, Wisconsin  54449
Comprehensive Cancer Institute Huntsville, Alabama  35801
Vermont Cancer Center at University of Vermont Burlington, Vermont  05405-0075
Baptist Cancer Institute - Jacksonville Jacksonville, Florida  32207
Josephine Ford Cancer Center at Henry Ford Health System Detroit, Michigan  48202
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School New Brunswick, New Jersey  08903
MBCCOP-Medical College of Georgia Cancer Center Augusta, Georgia  30912-4000
William Beaumont Hospital - Royal Oak Royal Oak, Michigan  48073-6769
Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center Orange, California  92868
Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital Greenville, North Carolina  27858-4354
MBCCOP-Our Lady of Mercy Cancer Center Bronx, New York  10466
Helen and Harry Gray Cancer Center at Hartford Hospital Hartford, Connecticut  06102-5037
Florida Cancer Specialists Fort Myers, Florida  33901
M.D. Anderson Cancer Center - Orlando Orlando, Florida  32806
Genesis Regional Cancer Center at Genesis Medical Center Davenport, Iowa  52803
Providence Cancer Institute at Providence Hospital - Southfield Campus Southfield, Michigan  48075
Charles R. Wood Cancer Center at Glens Falls Hospital Glens Falls, New York  12801
Creticos Cancer Center at Advocate Illinois Masonic Medical Center Chicago, Illinois  60657
Missouri Baptist Cancer Center St. Louis, Missouri  63131
Akron City Hospital at Summa Health System Akron, Ohio  44304
South Pointe Hospital Cancer Care Center Warrensville Heights, Ohio  44122
John and Dorothy Morgan Cancer Center at Lehigh Valley Hospital Allentown, Pennsylvania  18105
Saint Louis University Cancer Center Saint Louis, Missouri  63110
Morton Plant Hospital Clearwater, Florida  33756
John H. Stroger, Jr. Hospital of Cook County Chicago, Illinois  60612-9985
Community Hospital Munster, Indiana  46321
Consultants in Blood Disorders and Cancer Louisville, Kentucky  40207
Stanley S. Scott Cancer Center at Louisiana State University Medical Center - New Orleans New Orleans, Louisiana  70112
Lincoln Medical and Mental Health Center Bronx, New York  10451
Alamance Cancer Center Burlington, North Carolina  27216
Phoebe Cancer Center at Phoebe Putney Memorial Hospital Albany, Georgia  31702
York Cancer Center at Wellspan Health York, Pennsylvania  17403
Pacific Shores Medical Group Comprehensive Hematology-Oncology Services - Long Beach Long Beach, California  90813
Rush Cancer Institute at Rush University Medical Center Chicago, Illinois  60612
David Lee Cancer Center at Charleston Area Medical Center Charleston, West Virginia  25304-1297
Comprehensive Cancer Center at Desert Regional Medical Center Palm Springs, California  92262
Cancer Research Network, Inc. Plantation, Florida  33324
Norton Cancer Center at Norton Hospital Louisville, Kentucky  40202-5070
New York Oncology Hematology, P.C. at Albany Regional Cancer Care Albany, New York  12208
Nalitt Cancer Institute at Staten Island University Hospital Staten Island, New York  10305
Cancer Center at Jewish Hospital Cincinnati, Ohio  45236
Cancer Care Center at Northside Medical Center Youngstown, Ohio  44501
Sentara Cancer Institute at Sentara Norfolk General Hospital Norfolk, Virginia  23507
Oncology Alliance, S.C. - Milwaukee Milwaukee, Wisconsin  53211-2906