Women with primary ErbB2 overexpressing and/or gene amplified breast cancer > 2 cm diameter who have not undergone previous treatment for invasive breast cancer MedDRA version: 20.0 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Female 2) Age =18 years 3) Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1 4) Histologically confirmed invasive breast cancer: - Primary tumour greater than 2 cm diameter, - Any Node, - No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed) 5) Over expression and/or gene amplification of ErbB2 in the invasive component of the primary tumour according to one of the following definitions and confirmed by a certified laboratory prior to randomisation: – 3+ over expression by IHC; – 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ hybridization (FISH/CISH) test demonstrating HER2 gene amplification; – HER2 gene amplification by FISH/CISH Patients with a negative or equivocal overall result and staining scores of 0, 1+, 2+ or 3+ (in 30% or less neoplastic cells) by IHC are not eligible Equivocal local results from non certified laboratories may be submitted for a final determination by the certified laboratory. ErbB2 status must be tested in local or regional certified laboratories prior to randomisation. Local testing performed in non-certified laboratories, will also need confirmation of the results by a certified laboratory. 6) Hormone receptor (HR) status: - Oestrogen Receptor (ER) status must be known. 7) Haematopoietic status: - Absolute neutrophil count =1.5 x 10^9/L, - Platelet count =100 x 10^9/L, - Hemoglobin at least 9 g/dl, 8) Hepatic status: - Bilirubin = 2 x upper limit of normal (ULN), - AST and ALT = 2.5 times ULN, - Alkaline phosphatase = 2.5 times ULN, 9) Renal status: - Creatinine = 2.0 mg/dL, 0) Cardiovascular: - Baseline LVEF = 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan, 11) Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential) 12) Fertile patients must use effective contraception as specified in the protocol 13) Signed informed consent form (ICF) 14) Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 403 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 52
Exclusion criteria
Exclusion criteria: 1) Received any prior treatment for primary invasive breast cancer; 2) History of other malignancy. However, subjects with a past or current history of completely resected basal and squamous cell carcinoma of the skin or successfully treated in situ carcinoma of the cervix are eligible; 3) Diagnosis of inflammatory breast cancer; 4) Bilateral cancer; 5) Multi-focal cancer; 6) Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, uncontrolled hypertension (= 180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen; 7) Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject’s safety; 8) Unresolved or unstable, serious adverse events from prior administration of another investigational drug; 9) Active or uncontrolled infection; 10) Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF; 11) Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; 12) Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies); 13) Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial; 14) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients; 15) Pregnant or lactating women; 16) Concomitant use of CYP3A4 inhibitors or inducers.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with ErbB2 overexpressing or amplified operable breast cancer randomised between the study treatment arms.;Secondary Objective: -To compare the safety and tolerability of the treatment arms; -To compare the objective response rate among the treatment arms at week 6 and at definitive surgery; -To compare the percent of patients with node-negative disease at surgery among the treatment arms; -To compare the rate of conversion to breast conserving surgery; -To compare the rate of conversion to breast surgery of patients with non-operable breast cancer; -To compare event free survival (EFS) and overall survival (OS) from randomization among the treatment arms; -To assess associations between locoregional pCR and EFS and between locoregional pCR and OS; -To identify the molecular characteristics of responding tumours; -To study biomarkers expression and correlate with outcome; -To establish associations between PET/CT, response, molecular changes; -To prospectively study the effect on CTCs; -To prospectively study the prognostic/predictive value of CTCs; -To study the clinical value of CTCs. ;Primary end point(s): To evaluate and compare the rate of pCR (according to NSABP guidelines) [Fisher, 1997; Fisher, 2002] at the time of surgery in patients with ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib in combination with trastuzumab plus paclitaxel.;Timepoint(s) of evaluation of this end point: At the time of surgery, approximately 18 weeks after starting anti-HER2 therapy and 12 weeks after starting chemotherapy combined with anti-HER2 therapy. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To compare the safety and tolerability of the three treatment arms; - To compare the objective response rate (complete plus partial) among the three treatment arms at the end of biological window (week 6) and at definitive surgery; - To compare the percent of patients with node-negative disease at surgery among the three treatment arms; - To compare the rate of conversion to breast conserving surgery among the three treatment arms; - To compare the rate of conversion to breast surgery of patients with non-operable breast cancer among the three treatment arms; - To compare event free survival (EFS) and overall survival (OS) from randomization among the three treatment arms; - To assess associations between locoregional pCR and EFS and between locoregional pCR and OS using a more stringent definition of locoregional pCR defined as absence of invasive disease in both the breast and ipsilateral sampled lymph nodes (ypT0/is ypN0); - To identify the molecular characteristics of responding tumours by immunohistochemical, FISH, genomic and proteomic analysis; - To study biomarkers expression before and during therapy and establish correlations with clinical outcome; -Wherever possible to establish associations between PET/CT, tumour response and molecular changes, and to hypothesize about association with number of CTCs and about the predictive value of early PET/CT imaging for evaluation of response to targeted anti-ErbB2 therapies; - To prospectively study the effect of biologic agents (lapatinib, trastuzumab, or their combination) on CTCs; - To prospectively study the prognostic/predictive value of monitoring CTCs in patients with breast cancer; - To study the clinical value of CTCs within the context of tumour molecular and metabolic changes in patients receiving anti-HER2 therapies. | — |
Countries
Argentina, Belgium, Brazil, Canada, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, India, Italy, Korea, Republic of, Lithuania, Norway, Peru, Romania, Russian Federation, South Africa, Spain, Sweden, Taiwan, Ukraine, United Kingdom
Contacts
Public ContactClinical Trial Information Desk
SIA Novartis Baltics Lithuanian Branch
Outcome results
None listed