HER2 positive metastatic breast cancer MedDRA version: 17.0 Level: PT Classification code 10065430 Term: HER-2 positive breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
F. Hoffmann-La Roche Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Disease specific inclusion criteria: 1. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Patients with measurable and/or non-measurable disease are eligible. Patients with only bone metastases are eligible provided that they have some bone metastases that have not been previously irradiated and tumor tissue samples from the primary tumor are available for central HER 2 testing and subsequent biomarkers analysis. Locally recurrent disease must not be amenable to resection with curative intent. Note: Patients with de novo Stage IV disease are eligible. 2. HER2-positive (defined as 3+ IHC or FISH amplification ratio = 2.0 ) MBC confirmed by a Sponsor-designated central laboratory. It is recommended that a formalin-fixed paraffin-embedded (FFPE) tissue block from the primary tumor (or metastatic if the primary is not available) be submitted for central laboratory confirmation of HER2 eligibility; however, if that is not possible, 25 unstained and freshly cut slides will be submitted. (Tissue will subsequently be used for assessment of biomarkers.) General inclusion criteria: 3. Age = 18 years 4. Left Ventricular Ejection Fraction (LVEF) >= 50% at baseline (within 42 days of randomization) as determined by either ECHO or MUGA (ECHO is the preferred method. If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study, and to the extent possible, be obtained at the same institution) (see Section 7.4.2 of the protocol). All pre-study LVEF values during and post-trastuzumab adjuvant treatment for patients who received such adjuvant therapy prior to enrollment into the study will be collected. 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 6. For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly-effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner. Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the pregnancy. For further details see Section 7.2.6. 7. Signed, written informed consent (approved by the Institutional Review Board or Independent Ethics Committee) obtained prior to any study procedure. 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 681 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 127
Exclusion criteria
Exclusion criteria: Cancer Related Exclusion Criteria: 1. History of anticancer therapy for MBC (with the exception of one prior hormonal regimen for MBC which must be stopped prior to randomization). Anticancer therapy for MBC includes any EGFR or anti-HER2 agents or vaccines, cytotoxic chemotherapy, or more than one prior hormonal regimen for MBC. One prior hormonal “regimen” for MBC may include more than one hormonal therapy, for example, if the switch is not related to disease progression, such as toxicity or local standard practice, this will be counted as one “regimen”. If a patient receives hormonal therapy for MBC and is switched to a different hormonal therapy due to disease progression, this will be counted as two “regimens” and the patient is not eligible. 2. History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting 3. History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of 360 mg/m2 •epirubicin > 720 mg/m2 •mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2 •Other (e.g., liposomal doxorubicin or other anthracycline > the equivalent of 360 mg/m2 of doxorubicin) •If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin. Hematological, Biochemical, and Organ Function 9. Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina 10. History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia) 11. History of myocardial infarction within 6 months of randomization 12. History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy 13. Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy General Exclusion Criteria 14. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization: •Absolute neutrophil count < 1,500 cells/mm3 •Pla
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare progression-free survival (PFS) based on tumor assessments by an independent review facility (IRF) between patients in the two treatment arms.; Secondary Objective: • To compare overall survival (OS) between the two treatment arms • To compare PFS between the two treatment arms based upon investigator assessment of progression • To compare the overall objective response rate between the two treatment arms • To compare the duration of objective response between the two treatment arms • To compare the safety profile between the two treatment arms (including crossover patients and those no longer receiving placebo) • To compare time to symptom progression, as assessed by the FACT Trial Outcome Index - Physical Functional Breast (TOI-PFB) • To evaluate if biomarkers from tumor tissues or blood samples (e.g., HER3 expression, Fc gamma, and serum ECD/HER2 and/or HER ligands concentrations) correlate with clinical outcomes ;Primary end point(s): Progression-free survival (PFS) based on Independent Review Facility (IRF) evaluations. PFS is defined as the time from randomization to the first documented progressive disease, as determined by the IRF using RECIST (Therasse et al. 2000), or death from any cause, whichever occurs first. Assessments will be based on review of radiographic (e.g., MRI, CT, bone scans, chest x-ray, etc.), as well as cytologic (e.g., relevant cytology reports documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal fluid, etc.), and photographic data, if available, generated from all patients.;Timepoint(s) of evaluation of this end point: The primary analysis of the primary endpoint will take place when approximately 381 IRF-assessed PFS events have occurred. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Overall survival: OS is defined as the time from the date of randomization to the date of death from any cause. -PFS based on investigator assessment: PFS based on investigator assessment is defined as the time from randomization to the first documented radiographic progressive disease, as determined by the investigator using current RECIST (Therasse et al. 2000), or death from any cause, whichever comes first. Carcinomatous meningitis diagnosed by cytologic evaluation of cerebral spinal fluid will also define progressive disease. Medical photography will also be allowed to monitor chest wall recurrences of subcutaneous lesions. -Objective response: Objective response is defined as a CR or PR determined by the IRF using current RECIST (Therasse et al. 2000) on two consecutive occasions >= 4 weeks apart. Patients with disease localized only to the bone will not be included in the analysis of objective response. -Duration of response: Duration of response is defined as the period from the date of initial confirmed PR or CR until the date of progressive disease or death from any cause. Tumor responses will be based on the IRF evaluations using current RECIST (Therasse et al. 2000). -Time to symptom progression: This is defined as the time from randomization to the first symptom progression in the FACT TOI-PFB. The TOI-PFB is a 24-item subscale generated using 3 subsections from the FACT-B questionnaire: Physical Well-being, Functional Well-being and Additional Concerns. A decrease of five points is considered clinically significant, and thus symptom progression. -Biomarker analysis: The relationship between molecular markers and efficacy outcomes will be evaluated ;Timepoint(s) of evaluation of this end point: Once there have been 385 deaths | — |
Countries
Argentina, Brazil, Canada, China, Costa Rica, Croatia, Ecuador, European Union, Finland, France, Germany, Guatemala, Hong Kong, Italy, Japan, Korea, Republic of, Latvia, Macedonia, the former Yugoslav Republic of, Mexico, Philippines, Russian Federation, Singapore, Spain, Thailand, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd.
Outcome results
None listed