A Study of AC Followed by a Combination of Paclitaxel Plus Trastuzumab or Lapatinib or Both Given Before Surgery to Patients With Operable HER2 Positive Invasive Breast Cancer
- Conditions
- Invasive Breast Cancer
- Interventions
- Registration Number
- NCT00486668
- Lead Sponsor
- NSABP Foundation Inc
- Brief Summary
The primary purpose of this study is to determine whether breast cancer tumors respond (as measured by pathologic complete response: the absence of microscopic evidence of invasive tumor cells in the breast) to combined chemotherapy of AC(doxorubicin and cyclophosphamide) followed by paclitaxel plus trastuzumab or lapatinib or both given before surgery to patients with HER2-positive breast cancer. Trastuzumab will also be given to all patients after surgery. The study will also evaluate the toxic effects of the chemotherapy combination, including effects on the heart, and will determine survival and progression-free survival 5 years after treatment. Also, the study will look at whether there are gene expression profiles in the tumor tissue that can predict pathologic complete response.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 529
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 1: AC then paclitaxel + trastuzumab doxorubicin AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab cyclophosphamide AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab paclitaxel AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab trastuzumab AC followed by paclitaxel plus trastuzumab Group 2: AC then paclitaxel + lapatinib doxorubicin AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib cyclophosphamide AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib paclitaxel AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib lapatinib AC followed by paclitaxel plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib doxorubicin AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib trastuzumab AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib cyclophosphamide AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib paclitaxel AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib lapatinib AC followed by paclitaxel plus trastuzumab plus lapatinib
- Primary Outcome Measures
Name Time Method Determination of pathologic complete response (pCR), defined by the absence of microscopic evidence of invasive tumor cells in the post chemotherapy surgical breast specimen. surgery following chemotherapy
- Secondary Outcome Measures
Name Time Method The determination of pCR in the surgical breast and lymph node specimens following chemotherapy. surgery following chemotherapy Clinical tumor measurement as assessed by physical exam of the breast and lymph nodes baseline (prior to starting protocol therapy), at the completion of AC (before starting paclitaxel and trastuzumab and/or lapatinib), and at the conclusion of the sequential regimens (prior to surgery). Determination of cardiac toxicity as measured by the incidence of cardiac events defined as definite or probable cardiac death two year cumulative incidence Determination of non-cardiac toxicities as measured by frequencies of adverse events categorized using CTCAE v3.0. through 5 years after entry Overall survival as measured by time from randomization until death from any cause. through 5 years after entry Recurrence-free interval as measured by occurrence of inoperable progressive disease, or from time of surgery to occurrence of local, regional, or distant recurrence in patients with operable disease. through 5 years after entry In tumor tissue, a comparison of array comparative genomic hybridization (CGH) data with gene expression profile data to examine coordinated overexpression of amplified genes, especially in HER2 and cMYC loci. Tissue sample collected at surgery following chemotherapy
Trial Locations
- Locations (110)
CCOP, William Beaumont Hospital
🇺🇸Royal Oak, Michigan, United States
CCOP, Hematology-Oncology Associates of CNY
🇺🇸Syracuse, New York, United States
Lehigh Valley Hospital
🇺🇸Allentown, Pennsylvania, United States
CCOP, Upstate Carolina
🇺🇸Spartanburg, South Carolina, United States
Stanford University Medical Center
🇺🇸Palo Alto, California, United States
Hartford Hospital
🇺🇸Hartford, Connecticut, United States
MBCCOP, Gulf Coast
🇺🇸Mobile, Alabama, United States
Scripps Cancer Center-San Diego
🇺🇸La Jolla, California, United States
Reading Hospital & Medical Center
🇺🇸West Reading, Pennsylvania, United States
MBCCOP, Medical College of Georgia Research Institute
🇺🇸Augusta, Georgia, United States
Kaiser Permanente Rock Creek
🇺🇸Lafayette, Colorado, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
CCOP, Ozark Health Ventures LLC
🇺🇸Springfield, Missouri, United States
Memorial Hospital
🇺🇸Colorado Springs, Colorado, United States
Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
CCOP, Northern Indiana Cancer Research Consortium
🇺🇸South Bend, Indiana, United States
CCOP, Sioux Community Cancer consortium
🇺🇸Sioux City, Iowa, United States
CCOP, Montana Cancer Consortium
🇺🇸Billings, Montana, United States
Sibley Memorial Hospital
🇺🇸Washington, District of Columbia, United States
Michigan State University - Breslin Cancer Center
🇺🇸Lansing, Michigan, United States
Cancer Institute at Alexian Brothers Hospital Network
🇺🇸Elk Grove, Illinois, United States
Edward Cancer Center Plainfield
🇺🇸Plainfield, Illinois, United States
CCOP, Kalamazoo, MI
🇺🇸Kalamazoo, Michigan, United States
CCOP, Southeast Cancer Control Consortium
🇺🇸Charlotte, North Carolina, United States
Providence Hospital - Southfield
🇺🇸Southfield, Michigan, United States
Saint Louis UniversityHealth Sciences Center
🇺🇸St. Louis, Missouri, United States
Alamance Regional Medical Center
🇺🇸Burlington, North Carolina, United States
University of Missouri-Ellis Fischel
🇺🇸Columbia, Missouri, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
CCOP, Dayton, OH
🇺🇸Dayton, Ohio, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Akron City Hospital
🇺🇸Akron, Ohio, United States
CCOP, Northwest
🇺🇸Tacoma, Washington, United States
Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement
🇨🇦Quebec City, Quebec, Canada
Kootenai Cancer Center
🇺🇸Coeur D'Alene, Idaho, United States
Phoebe Putney Memorial Hospital
🇺🇸Albany, Georgia, United States
Western Pennsylvania Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
CCOP, Grand Rapids Clnical Oncology Program
🇺🇸Grand Rapids, Michigan, United States
Aultman Hospital
🇺🇸Canton, Ohio, United States
Mercy Hospital
🇺🇸Scranton, Pennsylvania, United States
CCOP, Marshfield Clinic
🇺🇸Marshfield, Wisconsin, United States
CCOP, Main Line Health
🇺🇸Wynnewood, Pennsylvania, United States
St. Mary's Hospital Center
🇨🇦Montreal, Quebec, Canada
Wheeling Hospital
🇺🇸Wheeling, West Virginia, United States
West Virginia University Hospitals Inc.
🇺🇸Morgantown, West Virginia, United States
Albert Einstein Healthcare Network
🇺🇸Philadelphia, Pennsylvania, United States
New York Oncology Hematology PC-Albany
🇺🇸Albany, New York, United States
Sanford Cancer Center
🇺🇸Souix Falls, South Dakota, United States
Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
MBCCOP, San Juan, Puerto Rico
🇵🇷San Juan, Puerto Rico
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Camden-Clark Memorial Hospital
🇺🇸Parkersburg, West Virginia, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
CCOP, Columbus, OH
🇺🇸Columbus, Ohio, United States
NSABP Foundation, Inc.
🇺🇸Pittsburgh, Pennsylvania, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Case Western Reserve/University Hospitals-Ireland Cancer Cntr.
🇺🇸Cleveland, Ohio, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
Puget Sound Oncology Consortium
🇺🇸Seattle, Washington, United States
CCOP, Virginia Mason
🇺🇸Seattle, Washington, United States
St. Vincent Hospital and Health Care Center
🇺🇸Indianapolis, Indiana, United States
Greater Baltimore Medical Center
🇺🇸Baltimore, Maryland, United States
University of Hawaii
🇺🇸Honolulu, Hawaii, United States
Kaiser Permanente-San Diego
🇺🇸San Diego, California, United States
CCOP, Metro-Minnesota
🇺🇸Minneapolis, Minnesota, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Kaiser Permanente-Franklin
🇺🇸Denver, Colorado, United States
CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only)
🇺🇸Denver, Colorado, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Hennepin County Medical Center
🇺🇸Minneapolis, Minnesota, United States
CCOP, Missouri Valley Consortium
🇺🇸Omaha, Nebraska, United States
University of Colorado Cancer Center
🇺🇸Aurora, Colorado, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University of California, Irvine Medical Center
🇺🇸Long Beach, California, United States
Pacific Shores Medical Group
🇺🇸Long Beach, California, United States
Desert Regional Medical Center Comprehensive Cancer Center
🇺🇸Palm Springs, California, United States
Santa Rosa Memorial Hospital
🇺🇸Santa Rosa, California, United States
Sutter Medical Center
🇺🇸Sacramento, California, United States
St. Joseph Hospital
🇺🇸Orange, California, United States
Kaiser Permanente-Vallejo
🇺🇸Vallejo, California, United States
Eastern Connecticut Hematology & Oncology Associates
🇺🇸Norwich, Connecticut, United States
CCOP, Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Edward Hospital
🇺🇸Naperville, Illinois, United States
CCOP, Central Illinois
🇺🇸Springfield, Illinois, United States
CCOP, Wichita KS
🇺🇸Wichita, Kansas, United States
Franklin Square Hospital Center
🇺🇸Baltimore, Maryland, United States
CCOP, Heartland Cancer Research
🇺🇸St. Louis, Missouri, United States
Cancer Center at Glens Falls Hospital
🇺🇸Glens Falls, New York, United States
Wake Forest University School of Medicine
🇺🇸Winston-Salem, North Carolina, United States
Alamance Regional Medical Center - Off site Clinic
🇺🇸Mebane, North Carolina, United States
CCOP, Oklahoma
🇺🇸Tulsa, Oklahoma, United States
Geisinger Clinic
🇺🇸Danville, Pennsylvania, United States
Allegheny General Hospital/Allegheny-Singer Research Institute
🇺🇸Pittsburgh, Pennsylvania, United States
Joe Arrington Cancer Research & Treatment Center
🇺🇸Lubbock, Texas, United States
Thompson Cancer Survival Center-Dowell Springs
🇺🇸Knoxville, Tennessee, United States
Odette Cancer Centre
🇨🇦Toronto, Ontario, Canada
Royal Victoria Hospital
🇨🇦Montreal, Quebec, Canada
University of Montreal Hospital Group
🇨🇦Montreal, Quebec, Canada
MD Anderson Cancer Center
🇺🇸Orlando, Florida, United States
Kaiser Permanente Hawaii - Moanalua Med Center
🇺🇸Honolulu, Hawaii, United States
MBCCOP, Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
NortonHealtcare Inc.
🇺🇸Louisville, Kentucky, United States
CCOP, Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
CCOP, Michigan Cancer Research Consortium
🇺🇸Ann Arbor, Michigan, United States
CCOP, Kansas City (Administrative Only)
🇺🇸Kansas City, Missouri, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
CCOP, Des Moines, IA
🇺🇸Des Moines, Iowa, United States
University of Kentucky Medical Center
🇺🇸Lexington, Kentucky, United States