Clinical trial NCT00486668: 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
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Invasive Breast Cancer
Keywords: HER2 positive breast cancer
invasive breast cancer
lapatinib
neoadjuvant
NSABP
paclitaxel
trastuzumab
doxorubicin
cyclophosphamide
Lead sponsor: NSABP Foundation Inc
Sponsor class: NETWORK
Collaborators: name: GlaxoSmithKline
First posted: 2007-06-15
Enrollment: 529
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
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.
timeFrame: surgery following chemotherapy
Secondary outcomes:
measure: The determination of pCR in the surgical breast and lymph node specimens following chemotherapy.
timeFrame: surgery following chemotherapy
measure: Clinical tumor measurement as assessed by physical exam of the breast and lymph nodes
timeFrame: 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).
measure: Determination of cardiac toxicity as measured by the incidence of cardiac events defined as definite or probable cardiac death
timeFrame: two year cumulative incidence
measure: Determination of non-cardiac toxicities as measured by frequencies of adverse events categorized using CTCAE v3.0.
timeFrame: through 5 years after entry
measure: Overall survival as measured by time from randomization until death from any cause.
timeFrame: through 5 years after entry
measure: 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.
timeFrame: through 5 years after entry
measure: 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.
timeFrame: Tissue sample collected at surgery following chemotherapy
Other outcomes:
Locations:
city: Mobile
country: United States
facility: MBCCOP, Gulf Coast
state: Alabama
city: La Jolla
country: United States
facility: Scripps Cancer Center-San Diego
state: California
city: Long Beach
country: United States
facility: University of California, Irvine Medical Center
state: California
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: Orange
country: United States
facility: St. Joseph Hospital
state: California
city: Palm Springs
country: United States
facility: Desert Regional Medical Center Comprehensive Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter Medical Center
state: California
city: San Diego
country: United States
facility: Kaiser Permanente-San Diego
state: California
city: Santa Rosa
country: United States
facility: Santa Rosa Memorial Hospital
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente-Vallejo
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Colorado Springs
country: United States
facility: Memorial Hospital
state: Colorado
city: Denver
country: United States
facility: Kaiser Permanente-Franklin
state: Colorado
city: Denver
country: United States
facility: CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only)
state: Colorado
city: Lafayette
country: United States
facility: Kaiser Permanente Rock Creek
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Norwich
country: United States
facility: Eastern Connecticut Hematology & Oncology Associates
state: Connecticut
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Orlando
country: United States
facility: MD Anderson Cancer Center
state: Florida
city: Albany
country: United States
facility: Phoebe Putney Memorial Hospital
state: Georgia
city: Augusta
country: United States
facility: MBCCOP, Medical College of Georgia Research Institute
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Honolulu
country: United States
facility: Kaiser Permanente Hawaii - Moanalua Med Center
state: Hawaii
city: Coeur D'Alene
country: United States
facility: Kootenai Cancer Center
state: Idaho
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Elk Grove
country: United States
facility: Cancer Institute at Alexian Brothers Hospital Network
state: Illinois
city: Naperville
country: United States
facility: Edward Hospital
state: Illinois
city: Plainfield
country: United States
facility: Edward Cancer Center Plainfield
state: Illinois
city: Springfield
country: United States
facility: CCOP, Central Illinois
state: Illinois
city: Urbana
country: United States
facility: CCOP, Carle Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: St. Vincent Hospital and Health Care Center
state: Indiana
city: South Bend
country: United States
facility: CCOP, Northern Indiana Cancer Research Consortium
state: Indiana
city: Des Moines
country: United States
facility: CCOP, Des Moines, IA
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Sioux City
country: United States
facility: CCOP, Sioux Community Cancer consortium
state: Iowa
city: Wichita
country: United States
facility: CCOP, Wichita KS
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: NortonHealtcare Inc.
state: Kentucky
city: New Orleans
country: United States
facility: CCOP, Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Franklin Square Hospital Center
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: CCOP, Michigan Cancer Research Consortium
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: CCOP, Grand Rapids Clnical Oncology Program
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP, Kalamazoo, MI
state: Michigan
city: Lansing
country: United States
facility: Michigan State University - Breslin Cancer Center
state: Michigan
city: Royal Oak
country: United States
facility: CCOP, William Beaumont Hospital
state: Michigan
city: Southfield
country: United States
facility: Providence Hospital - Southfield
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: CCOP, Metro-Minnesota
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri-Ellis Fischel
state: Missouri
city: Kansas City
country: United States
facility: CCOP, Kansas City (Administrative Only)
state: Missouri
city: Springfield
country: United States
facility: CCOP, Ozark Health Ventures LLC
state: Missouri
city: St. Louis
country: United States
facility: Saint Louis UniversityHealth Sciences Center
state: Missouri
city: St. Louis
country: United States
facility: CCOP, Heartland Cancer Research
state: Missouri
city: Billings
country: United States
facility: CCOP, Montana Cancer Consortium
state: Montana
city: Omaha
country: United States
facility: CCOP, Missouri Valley Consortium
state: Nebraska
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Albany
country: United States
facility: New York Oncology Hematology PC-Albany
state: New York
city: Glens Falls
country: United States
facility: Cancer Center at Glens Falls Hospital
state: New York
city: Syracuse
country: United States
facility: CCOP, Hematology-Oncology Associates of CNY
state: New York
city: Burlington
country: United States
facility: Alamance Regional Medical Center
state: North Carolina
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: CCOP, Southeast Cancer Control Consortium
state: North Carolina
city: Mebane
country: United States
facility: Alamance Regional Medical Center - Off site Clinic
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University School of Medicine
state: North Carolina
city: Akron
country: United States
facility: Akron City Hospital
state: Ohio
city: Canton
country: United States
facility: Aultman Hospital
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve/University Hospitals-Ireland Cancer Cntr.
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Columbus
country: United States
facility: CCOP, Columbus, OH
state: Ohio
city: Dayton
country: United States
facility: CCOP, Dayton, OH
state: Ohio
city: Tulsa
country: United States
facility: CCOP, Oklahoma
state: Oklahoma
city: Allentown
country: United States
facility: Lehigh Valley Hospital
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Clinic
state: Pennsylvania
city: Hershey
country: United States
facility: Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Healthcare Network
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital/Allegheny-Singer Research Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: NSABP Foundation, Inc.
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Scranton
country: United States
facility: Mercy Hospital
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital & Medical Center
state: Pennsylvania
city: Wynnewood
country: United States
facility: CCOP, Main Line Health
state: Pennsylvania
city: Spartanburg
country: United States
facility: CCOP, Upstate Carolina
state: South Carolina
city: Souix Falls
country: United States
facility: Sanford Cancer Center
state: South Dakota
city: Knoxville
country: United States
facility: Thompson Cancer Survival Center-Dowell Springs
state: Tennessee
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research & Treatment Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Richmond
country: United States
facility: MBCCOP, Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Puget Sound Oncology Consortium
state: Washington
city: Seattle
country: United States
facility: CCOP, Virginia Mason
state: Washington
city: Tacoma
country: United States
facility: CCOP, Northwest
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Hospitals Inc.
state: West Virginia
city: Parkersburg
country: United States
facility: Camden-Clark Memorial Hospital
state: West Virginia
city: Wheeling
country: United States
facility: Wheeling Hospital
state: West Virginia
city: Marshfield
country: United States
facility: CCOP, Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: St. Mary's Hospital Center
state: Quebec
city: Montreal
country: Canada
facility: University of Montreal Hospital Group
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement
state: Quebec
city: San Juan
country: Puerto Rico
facility: MBCCOP, San Juan, Puerto Rico
Study officials:
affiliation: NSABP Foundation Inc
name: Norman Wolmark, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.