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A Randomized Phase III Trial of Neoadjuvant Therapy for Patients With Palpable and Operable HER2-Positive Breast Cancer Comparing the Combination of Trastuzumab Plus Lapatinib to Trastuzumab and to Lapatinib Administered With Weekly Paclitaxel Following AC Accompanied by Correlative Science Studies to Identify Predictors of Pathologic Complete Response


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

Thank you

Trial Information

A Randomized Phase III Trial of Neoadjuvant Therapy for Patients With Palpable and Operable HER2-Positive Breast Cancer Comparing the Combination of Trastuzumab Plus Lapatinib to Trastuzumab and to Lapatinib Administered With Weekly Paclitaxel Following AC Accompanied by Correlative Science Studies to Identify Predictors of Pathologic Complete Response


Women with breast cancers that overexpress HER2 are at greater risk for disease progression
and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant
humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks
downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in
women with metastatic and early-stage HER2-positive breast cancers. Because resistance to
trastuzumab eventually results in progressive disease in the metastatic setting and
contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to
develop agents other than trastuzumab that target HER2 signaling through different
mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor
of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in
preclinical studies and activity in women with HER2-positive, metastatic breast cancer that
has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of
HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the
intracellular domains of HER2 and EGFR and prevents activation of downstream signaling
pathways. Because of this different mechanism of action, lapatinib may be effective in
trastuzumab-resistant disease. The study will also provide important safety information on
trastuzumab and lapatinib combinations immediately following anthracycline exposure, and
also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib
when incorporated into a standard sequential AC followed by weekly paclitaxel (neo)adjuvant
regimen.

Availability of a second agent that can interrupt HER2-signaling pathways through completely
different mechanisms than those of trastuzumab offers the potential for further improvement
in the management of patients with HER2-overexpressing breast cancer in both the adjuvant
and metastatic setting. Co-administration of both trastuzumab and lapatinib with
chemotherapy may be important in improving outcomes in subsets of HER2-positive breast
cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may
increase toxicity, so it will be important to identify the subsets of patients who would
benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient
for many patients as evidenced by the results of the trastuzumab trials. Therefore,
co-administration to unselected populations of women with HER2-positive breast cancers would
not represent an optimal approach. Given the activity of lapatinib, it is likely that it
will also be sufficiently active in inhibiting HER2-pathway activation in some patients to
allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also
derive greater benefit from one of the HER2-blocking agents relative to the other.
Identification of potential predictive factors for pathologic complete response to the
combination or to either agent administered alone in neoadjuvant trials would provide
important information for adjuvant trials designed to definitively address these important
issues.

This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus
trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by
paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast
cancer.

Inclusion Criteria


Inclusion criteria:

- Female

- 18 years or older

- ECOG performance status of 0 or 1

- Primary breast tumor palpable and measures greater than or equal to 2.0 cm by
physical exam

- Diagnosis of invasive adenocarcinoma made by core needle biopsy

- Breast cancer determined to be HER2-positive

- LVEF assessment by MUGA scan or ECG within 3 months prior to randomization

- Blood counts must meet the following criteria:

- ANC greater than or equal to 1200/mm3

- Platelet count greater than or equal to 100,000/mm3

- Hemoglobin greater than or equal to 10 g/dL

- Serum creatinine less than or equal to ULN for the lab

- Adequate hepatic function by these criteria:

- Total bilirubin less than or equal to the ULN for the lab unless the patient has
a bilirubin elevation greater than ULN to 1.5 x ULN resulting from Gilbert's
disease or similar syndrome due to slow conjugation of bilirubin; and

- Alkaline phosphatase less than or equal to 2.5 x ULN; and

- AST less than or equal to 1.5 x ULN for the lab.

- If skeletal pain present or alkaline phosphatase greater than ULN (but less than or
equal to 2.5 x ULN), bone scan or PET scan must not demonstrate metastatic disease

- If AST or alkaline phosphatase greater than ULN , liver imaging (CT, MRI or PET scan)
must not demonstrate definitive metastatic disease and the requirements in criterion
for hepatic function must be met

- Able to swallow oral medications

Exclusion criteria:

- FNA alone to diagnose the primary tumor

- Excisional biopsy or lumpectomy was performed prior to randomization

- Surgical axillary staging procedure prior to randomization. Exceptions: 1) FNA or
core biopsy of an axillary node for any patient, and 2) although not recommended, a
pre-neoadjuvant therapy SN biopsy for patients with clinically negative axillary
nodes.

- Tumors clinically staged as T4

- Ipsilateral cN2b or cN3 disease (Patients with cN1 or cN2a disease are eligible)

- Definitive clinical or radiologic evidence of metastatic disease

- Synchronous bilateral invasive breast cancer

- Requirement for chronic use of any of the medications or substances specified in the
protocol

- Treatment including RT, chemotherapy, and/or targeted therapy for the currently
diagnosed breast cancer prior to randomization

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

- Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other
SERM. (Patients are eligible only if these medications are discontinued prior to
randomization)

- Prior history of breast cancer, including DCIS (Patients with a history of LCIS are
eligible)

- Prior therapy with anthracyclines, taxanes, trastuzumab, or lapatinib for any
malignancy

- Other malignancies unless the patient is considered to be disease-free for 5 or more
years prior to randomization and is deemed by her 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, carcinoma in situ
of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the
skin.

- Cardiac disease that would preclude the use of the drugs included in the B-41
treatment regimens. This includes but is not confined to:

- Active cardiac disease:

- angina pectoris requiring the use of anti-anginal medication;

- ventricular arrhythmias except for benign premature ventricular
contractions controlled by medication;

- conduction abnormality requiring a pacemaker;

- supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; and

- clinically significant valvular disease.

- History of cardiac disease:

- myocardial infarction;

- congestive heart failure; or

- cardiomyopathy.

- Uncontrolled hypertension, defined as blood pressure greater than 150/90 mm/Hg on
antihypertensive therapy

- History of or current symptomatic interstitial pneumonitis or pulmonary fibrosis or
definitive evidence of interstitial pneumonitis or pulmonary fibrosis described on CT
or chest x-ray in asymptomatic patients

- Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's
CTCAE v3.0

- Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel,
or other disease significantly affecting gastrointestinal function

- Other non-malignant systemic disease that would preclude treatment with any of the
treatment regimens or would prevent required follow-up

- Conditions that would prohibit administration of corticosteroids

- Administration of any investigational agents within 30 days before randomization

- Pregnancy or lactation

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:

Determination of pathologic complete response (pCR), defined by the absence of microscopic evidence of invasive tumor cells in the post chemotherapy surgical breast specimen.

Outcome Time Frame:

surgery following chemotherapy

Safety Issue:

No

Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.

Authority:

United States: Food and Drug Administration

Study ID:

NSABP B-41

NCT ID:

NCT00486668

Start Date:

July 2007

Completion Date:

July 2015

Related Keywords:

  • Invasive Breast Cancer
  • HER2 positive breast cancer
  • invasive breast cancer
  • lapatinib
  • neoadjuvant
  • NSABP
  • paclitaxel
  • trastuzumab
  • doxorubicin
  • cyclophosphamide
  • Breast Neoplasms

Name

Location

Akron City HospitalAkron, Ohio  44304
University of IowaIowa City, Iowa  52242
Stanford University Medical CenterStanford, California  94305-5408
University of Colorado Cancer CenterDenver, Colorado  80262
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
St. Vincent Hospital and Health Care CenterIndianapolis, Indiana  46260
Henry Ford HospitalDetroit, Michigan  48202
Medical College of WisconsinMilwaukee, Wisconsin  53226
Newark Beth Israel Medical CenterNewark, New Jersey  07112
Lehigh Valley HospitalAllentown, Pennsylvania  18103
Western Pennsylvania HospitalPittsburgh, Pennsylvania  15224
Rush University Medical CenterChicago, Illinois  60612-3824
Boston Medical CenterBoston, Massachusetts  02118
Providence Hospital - SouthfieldSouthfield, Michigan  48075-9975
Puget Sound Oncology ConsortiumSeattle, Washington  98109
Hartford HospitalHartford, Connecticut  06102-5037
Franklin Square Hospital CenterBaltimore, Maryland  21237
Camden-Clark Memorial HospitalParkersburg, West Virginia  26102
Cancer Institute of New JerseyNew Brunswick, New Jersey  08901
Sibley Memorial HospitalWashington, District of Columbia  20016
Memorial HospitalColorado Springs, Colorado  80909
Pacific Shores Medical GroupLong Beach, California  90813
Greater Baltimore Medical CenterBaltimore, Maryland  21204
University of PittsburghPittsburgh, Pennsylvania  15261
Desert Regional Medical Center Comprehensive Cancer CenterPalm Springs, California  92262
Hennepin County Medical CenterMinneapolis, Minnesota  
Henry Ford Health SystemDetroit, Michigan  48202
Cancer Center at Glens Falls HospitalGlens Falls, New York  12801
Ohio State UniversityColumbus, Ohio  43210
Albert Einstein Healthcare NetworkPhiladelphia, Pennsylvania  19141
University of Kentucky Medical CenterLexington, Kentucky  40536-0093
Decatur Memorial HospitalDecatur, Illinois  62526
Wake Forest University School of MedicineWinston-Salem, North Carolina  27157-1023
Hershey Medical CenterHershey, Pennsylvania  17033
Santa Rosa Memorial HospitalSana Rosa, California  95405
Kaiser Permanente-VallejoVallejo, California  94589
Phoebe Putney Memorial HospitalAlbany, Georgia  31703
University of HawaiiHonolulu, Hawaii  96813
Edward HospitalNaperville, Illinois  60566
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Alamance Regional Medical CenterBurlington, North Carolina  27216
Mercy HospitalScranton, Pennsylvania  18501
Wheeling HospitalWheeling, West Virginia  26003
University of North Carolina at Chapel HillChapel Hill, North Carolina  27599
University of California, Irvine Medical CenterOrange, California  92868
Aultman HospitalCanton, Ohio  44710
Kootenai Cancer CenterPost Falls, Idaho  83854
Geisinger ClinicDanville, Pennsylvania  17822
MD Anderson Cancer CenterOrlando, Florida  32806
Eastern Connecticut Hematology & Oncology AssociatesNorwich, Connecticut  06360
NSABP Foundation, Inc.Pittsburgh, Pennsylvania  15212
Kaiser Permanente-San DiegoSan Diego, California  92120
CCOP, Central IllinoisSpringfield, Illinois  62526
CCOP, Northern Indiana Cancer Research ConsortiumSouth Bend, Indiana  46601
NortonHealtcare Inc.Louisville, Kentucky  40202
CCOP, Grand Rapids Clnical Oncology ProgramGrand Rapids, Michigan  49503
CCOP, Michigan Cancer Research ConsortiumGrosse Pointe Woods, Michigan  48236
CCOP, Kalamazoo, MIKalamazoo, Michigan  49007
CCOP, Metro-MinnesotaMinneapolis, Minnesota  55416
CCOP, Southeast Cancer Control ConsortiumCharlotte, North Carolina  28203
Case Western Reserve/University Hospitals-Ireland Cancer Cntr.Cleveland, Ohio  44106
CCOP, Dayton, OHDayton, Ohio  45429
Allegheny General Hospital/Allegheny-Singer Research InstitutePittsburgh, Pennsylvania  15212
CCOP, Upstate CarolinaSpartanburg, South Carolina  29303
Joe Arrington Cancer Research & Treatment CenterLubbock, Texas  79410
MBCCOP, Virginia Commonwealth UniversityRichmond, Virginia  23298
CCOP, Marshfield ClinicMarshfield, Wisconsin  54449
MBCCOP, Gulf CoastMobile, Alabama  36608
Scripps Cancer Center-San DiegoLa Jolla, California  92037
St. Joseph HospitalOrange, California  92868
Sutter Medical CenterSacramento, California  95816
CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only)Denver, Colorado  80224
Kaiser Permanente-FranklinDenver, Colorado  80205
Kaiser Permanente Rock CreekLafayette, Colorado  80026
MBCCOP, Medical College of Georgia Research InstituteAugusta, Georgia  30912
Kaiser Permanente Hawaii - Moanalua Med CenterHonolulu, Hawaii  96819
Cancer Institute at Alexian Brothers Hospital NetworkElk Grove, Illinois  60007
Edward Cancer Center PlainfieldPlainfield, Illinois  60585
CCOP, Carle Cancer CenterUrbana, Illinois  61801
CCOP, Des Moines, IADes Moines, Iowa  52501
CCOP, Sioux Community Cancer consortiumSioux City, Iowa  51101
CCOP, Wichita KSWichita, Kansas  67214
CCOP, Ochsner Clinic FoundationNew Orleans, Louisiana  70121
CCOP, William Beaumont HospitalRoyal Oak, Michigan  48073
University of Missouri-Ellis FischelColumbia, Missouri  65203
CCOP, Kansas City (Administrative Only)Kansas City, Missouri  64131
CCOP, Ozark Health Ventures LLCSpringfield, Missouri  65804
CCOP, Heartland Cancer ResearchSt. Louis, Missouri  63131
Saint Louis UniversityHealth Sciences CenterSt. Louis, Missouri  63110
CCOP, Montana Cancer ConsortiumBillings, Montana  59101
CCOP, Missouri Valley ConsortiumOmaha, Nebraska  74136
New York Oncology Hematology PC-AlbanyAlbany, New York  12206
CCOP, Hematology-Oncology Associates of CNYSyracuse, New York  13057
Alamance Regional Medical Center - Off site ClinicMebane, North Carolina  27302
CCOP, Columbus, OHColumbus, Ohio  43215
CCOP, OklahomaTulsa, Oklahoma  74136
Reading Hospital & Medical CenterWest Reading, Pennsylvania  19612
CCOP, Main Line HealthWynnewood, Pennsylvania  19096
Sanford Cancer CenterSouix Falls, South Dakota  57104
Thompson Cancer Survival Center-Dowell SpringsKnoxville, Tennessee  37909
CCOP, Virginia MasonSeattle, Washington  99519
CCOP, NorthwestTacoma, Washington  83706
West Virginia University Hospitals Inc.Morgantown, West Virginia  26506-9162