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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

Information source: NSABP Foundation Inc
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Invasive Breast Cancer

Intervention: doxorubicin (Drug); cyclophosphamide (Drug); paclitaxel (Drug); trastuzumab (Drug); lapatinib (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: NSABP Foundation Inc

Official(s) and/or principal investigator(s):
Norman Wolmark, MD, Principal Investigator, Affiliation: NSABP Foundation Inc

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.

Clinical Details

Official title: 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

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

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

Secondary outcome:

The determination of pCR in the surgical breast and lymph node specimens following chemotherapy.

Clinical tumor measurement as assessed by physical exam of the breast and lymph nodes

Determination of cardiac toxicity as measured by the incidence of cardiac events defined as definite or probable cardiac death

Determination of non-cardiac toxicities as measured by frequencies of adverse events categorized using CTCAE v3.0.

Overall survival as measured by time from randomization until death from any cause.

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.

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.

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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

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

Locations and Contacts

MBCCOP, San Juan, Puerto Rico, San Juan 00936, Puerto Rico

MBCCOP, Gulf Coast, Mobile, Alabama 36608, United States

Scripps Cancer Center-San Diego, La Jolla, California 92037, United States

Pacific Shores Medical Group, Long Beach, California 90813, United States

University of California, Irvine Medical Center, Long Beach, California 90801, United States

St. Joseph Hospital, Orange, California 92868, United States

Desert Regional Medical Center Comprehensive Cancer Center, Palm Springs, California 92262, United States

Stanford University Medical Center, Palo Alto, California 94304, United States

Sutter Medical Center, Sacramento, California 95816, United States

Kaiser Permanente-San Diego, San Diego, California 92120, United States

Santa Rosa Memorial Hospital, Santa Rosa, California 95403, United States

Kaiser Permanente-Vallejo, Vallejo, California 94589, United States

University of Colorado Cancer Center, Aurora, Colorado 80045, United States

Memorial Hospital, Colorado Springs, Colorado 80909, United States

CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only), Denver, Colorado 80224, United States

Kaiser Permanente-Franklin, Denver, Colorado 80205, United States

Kaiser Permanente Rock Creek, Lafayette, Colorado 80026, United States

Hartford Hospital, Hartford, Connecticut 06102, United States

Eastern Connecticut Hematology & Oncology Associates, Norwich, Connecticut 06360, United States

Sibley Memorial Hospital, Washington, District of Columbia 20016, United States

MD Anderson Cancer Center, Orlando, Florida 32806, United States

Phoebe Putney Memorial Hospital, Albany, Georgia 31701, United States

MBCCOP, Medical College of Georgia Research Institute, Augusta, Georgia 30912, United States

Kaiser Permanente Hawaii - Moanalua Med Center, Honolulu, Hawaii 96819, United States

University of Hawaii, Honolulu, Hawaii 96813, United States

Kootenai Cancer Center, Coeur D'Alene, Idaho 83814, United States

Rush University Medical Center, Chicago, Illinois 60612, United States

Decatur Memorial Hospital, Decatur, Illinois 62526, United States

Cancer Institute at Alexian Brothers Hospital Network, Elk Grove, Illinois 60007, United States

Edward Hospital, Naperville, Illinois 60566, United States

Edward Cancer Center Plainfield, Plainfield, Illinois 60585, United States

CCOP, Central Illinois, Springfield, Illinois 62526, United States

CCOP, Carle Cancer Center, Urbana, Illinois 61801, United States

St. Vincent Hospital and Health Care Center, Indianapolis, Indiana 46260, United States

CCOP, Northern Indiana Cancer Research Consortium, South Bend, Indiana 46601, United States

CCOP, Des Moines, IA, Des Moines, Iowa 52501, United States

University of Iowa, Iowa City, Iowa 52242, United States

CCOP, Sioux Community Cancer consortium, Sioux City, Iowa 51101, United States

CCOP, Wichita KS, Wichita, Kansas 67214, United States

University of Kentucky Medical Center, Lexington, Kentucky 40536, United States

NortonHealtcare Inc., Louisville, Kentucky 40202, United States

CCOP, Ochsner Clinic Foundation, New Orleans, Louisiana 70121, United States

Franklin Square Hospital Center, Baltimore, Maryland 21237, United States

Greater Baltimore Medical Center, Baltimore, Maryland 21204, United States

Boston Medical Center, Boston, Massachusetts 02118, United States

CCOP, Michigan Cancer Research Consortium, Ann Arbor, Michigan 48106, United States

Henry Ford Health System, Detroit, Michigan 48202, United States

Henry Ford Hospital, Detroit, Michigan 48202, United States

CCOP, Grand Rapids Clnical Oncology Program, Grand Rapids, Michigan 49503, United States

CCOP, Kalamazoo, MI, Kalamazoo, Michigan 49007, United States

Michigan State University - Breslin Cancer Center, Lansing, Michigan 48910, United States

CCOP, William Beaumont Hospital, Royal Oak, Michigan 48073, United States

Providence Hospital - Southfield, Southfield, Michigan 48075-9975, United States

CCOP, Metro-Minnesota, Minneapolis, Minnesota 55416, United States

Hennepin County Medical Center, Minneapolis, Minnesota 55415, United States

University of Missouri-Ellis Fischel, Columbia, Missouri 65203, United States

CCOP, Kansas City (Administrative Only), Kansas City, Missouri 64131, United States

CCOP, Ozark Health Ventures LLC, Springfield, Missouri 65804, United States

CCOP, Heartland Cancer Research, St. Louis, Missouri 63131, United States

Saint Louis UniversityHealth Sciences Center, St. Louis, Missouri 63110, United States

CCOP, Montana Cancer Consortium, Billings, Montana 59101, United States

CCOP, Missouri Valley Consortium, Omaha, Nebraska 74136, United States

Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States

Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States

New York Oncology Hematology PC-Albany, Albany, New York 12206, United States

Cancer Center at Glens Falls Hospital, Glens Falls, New York 12801, United States

CCOP, Hematology-Oncology Associates of CNY, Syracuse, New York 13057, United States

Alamance Regional Medical Center, Burlington, North Carolina 27215, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 28302, United States

CCOP, Southeast Cancer Control Consortium, Charlotte, North Carolina 28203, United States

Alamance Regional Medical Center - Off site Clinic, Mebane, North Carolina 27302, United States

Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States

Akron City Hospital, Akron, Ohio 44304, United States

Aultman Hospital, Canton, Ohio 44710, United States

Case Western Reserve/University Hospitals-Ireland Cancer Cntr., Cleveland, Ohio 44106, United States

CCOP, Columbus, OH, Columbus, Ohio 43215, United States

Ohio State University, Columbus, Ohio 43017, United States

CCOP, Dayton, OH, Dayton, Ohio 45429, United States

CCOP, Oklahoma, Tulsa, Oklahoma 74136, United States

Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada

Lehigh Valley Hospital, Allentown, Pennsylvania 18105, United States

Geisinger Clinic, Danville, Pennsylvania 17882-2170, United States

Hershey Medical Center, Hershey, Pennsylvania 17033, United States

Albert Einstein Healthcare Network, Philadelphia, Pennsylvania 19141-3098, United States

Allegheny General Hospital/Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania 15212, United States

NSABP Foundation, Inc., Pittsburgh, Pennsylvania 15212, United States

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States

Western Pennsylvania Hospital, Pittsburgh, Pennsylvania 15224, United States

Mercy Hospital, Scranton, Pennsylvania 18501, United States

Reading Hospital & Medical Center, West Reading, Pennsylvania 19612, United States

CCOP, Main Line Health, Wynnewood, Pennsylvania 19096, United States

Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada

Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada

St. Mary's Hospital Center, Montreal, Quebec H3T 1M5, Canada

University of Montreal Hospital Group, Montreal, Quebec, Canada

Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement, Quebec City, Quebec G1S 4L8, Canada

CCOP, Upstate Carolina, Spartanburg, South Carolina 29303, United States

Sanford Cancer Center, Souix Falls, South Dakota 57104, United States

Thompson Cancer Survival Center-Dowell Springs, Knoxville, Tennessee 37909, United States

Joe Arrington Cancer Research & Treatment Center, Lubbock, Texas 79410, United States

University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States

MBCCOP, Virginia Commonwealth University, Richmond, Virginia 23298, United States

CCOP, Virginia Mason, Seattle, Washington 99519, United States

Puget Sound Oncology Consortium, Seattle, Washington 98109, United States

CCOP, Northwest, Tacoma, Washington 83706, United States

West Virginia University Hospitals Inc., Morgantown, West Virginia 26506-9162, United States

Camden-Clark Memorial Hospital, Parkersburg, West Virginia 26101, United States

Wheeling Hospital, Wheeling, West Virginia 26003, United States

CCOP, Marshfield Clinic, Marshfield, Wisconsin 54449, United States

Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States

Additional Information

Related publications:

Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, Margolese RG, Farrar WB, Brufsky AM, Shibata HR, Bandos H, Paik S, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1183-92. doi: 10.1016/S1470-2045(13)70411-X. Epub 2013 Oct 4.

Starting date: July 2007
Last updated: August 11, 2015

Page last updated: August 20, 2015

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