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

Invasive Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00486668
• Other study ID #: NSABP B-41
• Status: Active, not recruiting
• Phase: Phase 3
• First received: June 13, 2007
• Last updated: June 3, 2016
• Start date: July 2007
• Est. completion date: March 2017

Study information

• Verified date: June 2016
• Source: NSABP Foundation Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 529
• Est. completion date: March 2017
• Est. primary completion date: June 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Invasive Breast Cancer

Intervention

Drug:
• doxorubicin
60 mg/m2 IV every 21 days for cycles 1-4
• cyclophosphamide
600 mg/m2 IV every 21 days for cycles 1-4
• paclitaxel
80 mg/m2 IV on days 1, 8, and 15 every 28 days for cycles 5-8
• trastuzumab
First dose: 4 mg/kg IV, subsequent doses: 2 mg/kg IV weekly beginning on day 1 of the first paclitaxel cycle until 1-7 days before surgery
• lapatinib
Group 2: 1250 mg PO daily beginning on day 1 of the first paclitaxel cycle until 1 day before surgery. Group 3: 750 mg PO daily beginning on day 1 of the first paclitaxel cycle until 1 day before surgery.

Locations

Country	Name	City	State
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	St. Mary's Hospital Center	Montreal	Quebec
Canada	University of Montreal Hospital Group	Montreal	Quebec
Canada	Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement	Quebec City	Quebec
Canada	Odette Cancer Centre	Toronto	Ontario
Puerto Rico	MBCCOP, San Juan, Puerto Rico	San Juan
United States	Akron City Hospital	Akron	Ohio
United States	New York Oncology Hematology PC-Albany	Albany	New York
United States	Phoebe Putney Memorial Hospital	Albany	Georgia
United States	Lehigh Valley Hospital	Allentown	Pennsylvania
United States	CCOP, Michigan Cancer Research Consortium	Ann Arbor	Michigan
United States	MBCCOP, Medical College of Georgia Research Institute	Augusta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Franklin Square Hospital Center	Baltimore	Maryland
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	CCOP, Montana Cancer Consortium	Billings	Montana
United States	Boston Medical Center	Boston	Massachusetts
United States	Alamance Regional Medical Center	Burlington	North Carolina
United States	Aultman Hospital	Canton	Ohio
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	CCOP, Southeast Cancer Control Consortium	Charlotte	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Case Western Reserve/University Hospitals-Ireland Cancer Cntr.	Cleveland	Ohio
United States	Kootenai Cancer Center	Coeur D'Alene	Idaho
United States	Memorial Hospital	Colorado Springs	Colorado
United States	University of Missouri-Ellis Fischel	Columbia	Missouri
United States	CCOP, Columbus, OH	Columbus	Ohio
United States	Ohio State University	Columbus	Ohio
United States	Geisinger Clinic	Danville	Pennsylvania
United States	CCOP, Dayton, OH	Dayton	Ohio
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only)	Denver	Colorado
United States	Kaiser Permanente-Franklin	Denver	Colorado
United States	CCOP, Des Moines, IA	Des Moines	Iowa
United States	Henry Ford Health System	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Cancer Institute at Alexian Brothers Hospital Network	Elk Grove	Illinois
United States	Cancer Center at Glens Falls Hospital	Glens Falls	New York
United States	CCOP, Grand Rapids Clnical Oncology Program	Grand Rapids	Michigan
United States	Hartford Hospital	Hartford	Connecticut
United States	Hershey Medical Center	Hershey	Pennsylvania
United States	Kaiser Permanente Hawaii - Moanalua Med Center	Honolulu	Hawaii
United States	University of Hawaii	Honolulu	Hawaii
United States	St. Vincent Hospital and Health Care Center	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	CCOP, Kalamazoo, MI	Kalamazoo	Michigan
United States	CCOP, Kansas City (Administrative Only)	Kansas City	Missouri
United States	Thompson Cancer Survival Center-Dowell Springs	Knoxville	Tennessee
United States	Scripps Cancer Center-San Diego	La Jolla	California
United States	Kaiser Permanente Rock Creek	Lafayette	Colorado
United States	Michigan State University - Breslin Cancer Center	Lansing	Michigan
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	Pacific Shores Medical Group	Long Beach	California
United States	University of California, Irvine Medical Center	Long Beach	California
United States	NortonHealtcare Inc.	Louisville	Kentucky
United States	Joe Arrington Cancer Research & Treatment Center	Lubbock	Texas
United States	CCOP, Marshfield Clinic	Marshfield	Wisconsin
United States	Alamance Regional Medical Center - Off site Clinic	Mebane	North Carolina
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	CCOP, Metro-Minnesota	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	MBCCOP, Gulf Coast	Mobile	Alabama
United States	West Virginia University Hospitals Inc.	Morgantown	West Virginia
United States	Edward Hospital	Naperville	Illinois
United States	Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	CCOP, Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Eastern Connecticut Hematology & Oncology Associates	Norwich	Connecticut
United States	CCOP, Missouri Valley Consortium	Omaha	Nebraska
United States	St. Joseph Hospital	Orange	California
United States	MD Anderson Cancer Center	Orlando	Florida
United States	Desert Regional Medical Center Comprehensive Cancer Center	Palm Springs	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Camden-Clark Memorial Hospital	Parkersburg	West Virginia
United States	Albert Einstein Healthcare Network	Philadelphia	Pennsylvania
United States	Allegheny General Hospital/Allegheny-Singer Research Institute	Pittsburgh	Pennsylvania
United States	NSABP Foundation, Inc.	Pittsburgh	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	Edward Cancer Center Plainfield	Plainfield	Illinois
United States	MBCCOP, Virginia Commonwealth University	Richmond	Virginia
United States	CCOP, William Beaumont Hospital	Royal Oak	Michigan
United States	Sutter Medical Center	Sacramento	California
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Kaiser Permanente-San Diego	San Diego	California
United States	Santa Rosa Memorial Hospital	Santa Rosa	California
United States	Mercy Hospital	Scranton	Pennsylvania
United States	CCOP, Virginia Mason	Seattle	Washington
United States	Puget Sound Oncology Consortium	Seattle	Washington
United States	CCOP, Sioux Community Cancer consortium	Sioux City	Iowa
United States	Sanford Cancer Center	Souix Falls	South Dakota
United States	CCOP, Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	Providence Hospital - Southfield	Southfield	Michigan
United States	CCOP, Upstate Carolina	Spartanburg	South Carolina
United States	CCOP, Central Illinois	Springfield	Illinois
United States	CCOP, Ozark Health Ventures LLC	Springfield	Missouri
United States	CCOP, Heartland Cancer Research	St. Louis	Missouri
United States	Saint Louis UniversityHealth Sciences Center	St. Louis	Missouri
United States	CCOP, Hematology-Oncology Associates of CNY	Syracuse	New York
United States	CCOP, Northwest	Tacoma	Washington
United States	CCOP, Oklahoma	Tulsa	Oklahoma
United States	CCOP, Carle Cancer Center	Urbana	Illinois
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Reading Hospital & Medical Center	West Reading	Pennsylvania
United States	Wheeling Hospital	Wheeling	West Virginia
United States	CCOP, Wichita KS	Wichita	Kansas
United States	Wake Forest University School of Medicine	Winston-Salem	North Carolina
United States	CCOP, Main Line Health	Wynnewood	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
NSABP Foundation Inc	GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	The determination of pCR in the surgical breast and lymph node specimens following chemotherapy.		surgery following chemotherapy	No
Secondary	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).	No
Secondary	Determination of cardiac toxicity as measured by the incidence of cardiac events defined as definite or probable cardiac death		two year cumulative incidence	Yes
Secondary	Determination of non-cardiac toxicities as measured by frequencies of adverse events categorized using CTCAE v3.0.		through 5 years after entry	Yes
Secondary	Overall survival as measured by time from randomization until death from any cause.		through 5 years after entry	No
Secondary	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	No
Secondary	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	No