postmenopausal women with hormone receptor-positive, Her2 negative AI and fulvestrant treated, locally advanced or metastatic breast cancer, who progressed on prior fulvestrant and also received prior treatment with everolimus and exemestane. The treatment with fulvestrant is not required to be the last treatment administered as long as at some point in time a progression on fulvestrant has been ascertained. MedDRA version: 14.1 Level: LLT Classification code 10027475 Term: Metastatic breast c
Conditions
Interventions
Trade Name: Afinitor 5 mg tablets
Product Code: RAD001
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
CAS Number: 159351-69-6
Other descriptive name: EVEROLIMUS
Concentration unit: mg mil
Sponsors
UZ Brussel
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Postmenopausal women. Postmenopausal status is defined either by: - Age = 55 years and one year or more of amenorrhea - Age 100.000 10*6/L - WBC >3.5 and ANC> 1.5 10*9 g/L - Hb > 9.0 g/dL - INR 30 ml/min or Serum creatinine 18 years of age) with metastatic advanced breast cancer who relapse after adjuvant treatment treated with maximum of 3 lines of endocrine treatment. 8. For patients who present with metastatic disease at first diagnosis up to 4 lines of hormonal treatment before inclusion in the trial are accepted 9. Patients treated with maximum 1 line of chemotherapy for advanced disease. 10. Patient with histological or cytological confirmation of estrogen-receptor positive (ER+) or progesterone receptor positive (PR+) breast cancer 11. Patient with an ECOG Performance Status =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. HER2-overexpressing patients by local laboratory testing (FISH positive). 2. Known hypersensitivity to mTOR inhibitors. 3. Currently receiving hormone replacement therapy. 4. Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroid use; 5. Patients with symptomatic visceral disease in need of urgent disease control: e.g. significant dyspnea related to pulmonary lymphangitic carcinomatosis or lung metastases or clinically meaningful symptomatic liver metastasis at the judgment of treating investigator. 6. Metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan. 7. Symptomatic brain or other CNS metastases. Previously treated symptomatic brain metastases are allowed provided the patient is free of symptoms, prior radiotherapy for brain metastasis was more than four weeks before enrollment and the dose of corticosteroids is low and stable for at least two weeks prior to enrollment. 8. Patients with a known immunodeficiency disease. 9. Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment. 10. Patients with a known history of HIV seropositivity. 11. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the INR is = 2.0) 12. Any severe and / or uncontrolled medical conditions such as: • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =6 months prior to enrollment, serious uncontrolled cardiac arrhythmia • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN • Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy • Impairment of gastrointestinal function or gastrointestinal disease that may uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) • Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates. 13. Patients who test positive for hepatitis B or C. (Patients who test negative for HBV-DNA, HBsAg, and HBcAb but positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible) 14. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to enrollment 15. History of non-compliance to medical regimens 16. Patients unwilling to or unable to comply with the protocol. 17. ECOG score >2 18. Diagnosis of concurrent malignancy within 5 years of study enrollment, except for an adequately treated cervical carcinoma in situ and a basal or squamous cell carcinoma of the skin. 19. Patients with more than one line of prior chemotherapy for advanced disease 20. Patients with more than 3 lines of endocrine treatment for metastatic disease who relapse after adjuvant treatment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: A phase II academic study to investigate whether the combination of everolimus and fulvestrant can restore sensibility to fulvestrant in postmenopausal women with ER+ HER2- advanced breast cancer who received a previous everolimus + exemestane treatment;Timepoint(s) of evaluation of this end point: 16 weeks;Secondary Objective: - Determine the disease response to the combination of fulvestrant and everolimus. - The tolerability of the combination - Correlate the response with steady state plasma levels of everolimus (pharmacokinetic) at base line dosing and subsequent dose adaptations as determined one week after dosing initiation or subsequent dose adaptation. - Correlation of response with the activated mTOR pathway in tumor tissue. (biomarkers). - Correlation of early metabolic response with final outcome ;Primary end point(s): The primary endpoint is the 4-month clinical benefit rate (CBR) defined as the percentage of all patients with a complete or partial response or stable disease at 4 months with a duration of 16 weeks or longer, according to RECIST 1.1 criteria. Time to overall response (CR or PR) is the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 Duration of overall response applies only to patients whose best overall response is CR or PR. The start date is the date of first documented response (CR or PR) and the date is the date of event defined as first documented progression or death due to underlying cancer. See RECISTt 1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Response rate shall be evaluated using the RECIST 1.1 criteria. - The clinicians will report all the adverse events and grading using the CTC criteria version 4.0. - On day 8 a blood sample will be taken to measure the everolimus steady state plasma levels. - New tumour biopsies will be analyzed by immunohistochemistry and mutational analysis to make a correlation possible between tumour response and the activation of the mTor pathway and other biomarkers. - Early metabolic response will be determined by a Pet CT scan taken on day 14. ;Timepoint(s) of evaluation of this end point: For patient s with measurable disease at screening (as per RECIST criteria), efficacy (overall tumor response and progression) will be evaluated every 2 months (screening+3 evaluations) for 6 months and afterwards every 3 months. | — |
Countries
Belgium
Contacts
Public ContactDr Fontaine C.
UZ Brussel
Outcome results
None listed