Estrogen receptor or progesterone receptor positive locally advanced or metastatic breast cancer in postmenopausal women MedDRA version: 16.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
Conditions
Sponsors
Novartis Farmacéutica S. A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient signed informed consent both for study and sample cession. Written informed consent must be obtained before any trial related activity and according to local guidelines. 2. Post-menopausal women (>18 years of age) with metastatic or locally advanced unresectable disease. The patients must be treatment-naïve for advanced disease, although any agent is permitted during the adjuvant/neoadjuvant treatment. 3. Disease relapses at any time, during or after adjuvant therapy 4. Histopathological confirmation of hormone-receptor positive (estrogen-receptor positive (ER+) or progesterone receptor positive (PR+), defined as positivity of 10% in either of the receptors) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer. 5. Ductal or lobular breast cancer are allowed. 6. Available paraffin tumor sample at the time of diagnosis. Histologic confirmation of the disease site is also recommendable. In that case, if sufficient material is available after diagnosis, the sample should be sent to the sponsor. 7. Postmenopausal women. Postmenopausal status is defined either by: a. Age >55 years and one year or more of amenorrhea b. Age 20mm with conventional imaging techniques or >10mm with spiral CT or evaluable disease defined as bone lesions: lytic or mixed (lytic plus sclerotic) in the absence of measurable disease as defined above 10. Adequate bone marrow and coagulation function as shown by: a. Absolute neutrophil count (ANC) >1.5x109/L b. Platelets >100x109/L c. Hemoglobin (Hgb) >9.0g/dL d. INR 3 months 16. Loco-regional treatment (radiation, surgery) of one or more sites is allowed, as long as there are more non-treated sites prior to initiation of study treatment. 17. Ability to take oral medication and to comply with the study procedures. 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 53 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 53
Exclusion criteria
Exclusion criteria: 1. Patients with only non-measurable lesions other than bone metastasis as define above (e.g., pleural effusion, ascites, etc). 2. Patients who have received prior hormonal or any other systemic therapy for metastatic / advanced breast cancer. 3. HER-2 positive and triple-negative breast cancer. A first metastatic relapse event that is limited to a single site and has been treated with radical intention (surgery, radiation therapy, etc.) constitutes an exclusion criteria, including single-site brain metastasis. 4. Previous treatment with mTOR inhibitors. 5. Known hypersensitivity to mTOR inhibitors, e.g., sirolimus (rapamycin), everolimus or letrozole. 6. Neoadjuvant or adjuvant treatment termination due to intolerance to letrozole. 7. Lack of paraffin tumor sample from the initial breast cancer diagnosis. Patient is not eligible if only a post-neoadjuvant treatment sample is available. 8. Another malignancy within 5 years prior to enrollment with the exception of adequately treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer 9. Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose of lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. 10. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment 11. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below: Prolonged systemic corticosteroid treatment during study, except for topical applications (e.g. rash),inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intraarticular) should not be given. However, during the study: ? short duration (1.5xULN. c. Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) d. Active skin, mucosa, ocular or GI disorders of Grade >1 e. Uncontrolled Chronic Obstructive Pulmonary Disease f. Severe mental impairment g. Seizure h. Acute and chronic, active infectious disorders (except for Hep B and Hep C positive patients) and nonmalignant medical illness that are uncontrolled or whose control may be jeopardized by the complications of this study therapy i. Any other severe condition that according to the investigator could interfere with the administration of the study treatment. 16. Patients who have undergone major surgery within 4 weeks prior to starting study drug (e.g., intra-thoracic, intra-abdominal, or intra-pelvic). 17. Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary fu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to correlate the presence of biomarkers of the MTOR-activation pathway with the clinical efficacy of everolimus plus letrozole, defined as 6-month progression-free rate, in postmenopausal patients with hormone-receptor positive metastatic or locally advanced breast cancer in the first line setting;Secondary Objective: -To correlate the MTOR-activation pathway biomarkers with the clinical efficacy of everolimus plus letrozole, defined as progression-free survival -To correlate the presence of a hormonal resistance gene signature and immunohistochemistry markers of the mTOR pathway with the clinical efficacy defined as 6-month progression-free rate, PFS and ORR -To study retrospectively the correlation between presence of a gene-signature associated with sensitivity to everolimus and immunohistochemistry markers of the mTOR pathway with the clinical efficacy defined as 6-month progression-free rate, PFS and ORR -To evaluate progression free survival, overall response rate of everolimus + letrozole of the entire population in the first line setting -To evaluate the safety of everolimus plus letrozole -To assess the prevalence of biomarkers related with everolimus sensitivity and hormonal-resistance;Primary end point(s): The primary endpoint in this study is to determine the absence/presence of the MTOR-activation pathway biomarkers (pS6K, PI3K, pAkt and LKB1) in the paraffin samples which will be correlated with the 6-month progression-free rate by RECIST 1.1 criteria;Timepoint(s) of evaluation of this end point: Every two cycles (8 weeks) to registered disease progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -PFS rate by RECIST 1.1 criteria correlated with the absence/presence of the MTOR-activation pathway biomarkers (pS6K, PI3K, pAkt and LKB1) in the paraffin blocks (and fresh tissue biopsies if available) -To test the 6-months progression-free rate, PFS and ORR by RECIST 1.1 criteria correlated with absence/presence of the hormonal resistance genetic signature and immunohistochemistry markers of the mTOR pathway in paraffin blocks and fresh tissue biopsies -To test the 6-months progression-free rate, PFS and ORR by RECIST 1.1 criteria correlated with the absence/presence of the gene signature associated with sensitivity to everolimus and immunohistochemistry markers of the mTOR pathway retrospectively determined in the paraffin blocks and fresh tissue biopsies -Incidence of Adverse events. -Percentage of patients with biomarkers related with everolimus sensitivity and hormonal resistant.;Timepoint(s) of evaluation of this end point: -Every two cycles (8 weeks) to registered disease progression -Every two cycles (8 weeks) to registered disease progression -Every two cycles (8 weeks) to registered disease progression -Every visit -6 months after the last patient was recruited | — |
Countries
Spain
Contacts
Public ContactJavier Malpesa
Novartis Farmacéutica S.A.
Outcome results
None listed