The treatment of advanced breast cancer aims at reducing tumor size, slowing progression and metastasis and reducing complications such as fatigue, bone fracture and hypercalcemia. Women with tumors which are hormone dependent are candidates for endocrine therapies which have been shown to effectively delay disease progression and are much less toxic than cytotoxic chemotherapy. This study investigates the benefit of combining the antiendocrine drug letrozole (Femara®) and everolimus (RAD001).
Conditions
Sponsors
Novartis Pharma Services AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Adult women (= 18 years of age) with metastatic or locally recurrent breast cancer, not amenable to treatment by surgery or radiotherapy • Patients whose tumors express at least one hormone receptor (ER or PgR), as confirmed in the central laboratory • Patients must be postmenopausal as defined by any of the following criteria: 1. Radiation induced menopause or surgical bilateral oophorectomy 2. Women with an intact uterus and = 55 years of age or 9 g/dL • Adequate liver function as shown by: serum bilirubin = 1.5 x ULN, absence of ascites and encephalopathy due to liver disease, INR < 1.7, ALT and AST = 2.5x ULN ( = 5x ULN in patients with liver metastases). • Renal function: serum creatinine = 1.5 x ULN • Fasting serum cholesterol = 300 mg/dl or 7.75 mmol/L and fasting triglycerides = 2.5 x ULN. - In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy. • Performance Status 0-2 on the WHO scale • Signed consent to participate in the study must be obtained from patients after they have been fully informed on the nature and potential risks by the investigator with the aid of written informati
Exclusion criteria
Exclusion criteria: • Inflammatory breast cancer (histologically proven). • Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.) • Prior systemic endocrine treatment for advanced breast cancer (i.e. metastatic or locally recurrent breast cancer, not amenable to treatment by surgery or radiotherapy). Patients who had bilateral oophorectomy as the only antiendocrine intervention for advanced breast cancer can be included. • More than one prior regimen of chemotherapy for advanced breast cancer. • patients whose tumor relapsed during or within 12 months from the end of an adjuvant or neo-adjuvant therapy with an AI • Any neoadjuvant/adjuvant therapy with tamoxifen alone or in combination with chemotherapy within the past 4 weeks from randomization. • CNS metastases, bilateral diffuse lymphangitis carcinomatosa of the lung (>50% of lung involvement), evidence of metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan. • Patients in whom localized radiotherapy (for analgesic purposes) is considered an actual requirement (inclusion should be delayed until radiation therapy has been completed and the patient’s condition stabilized). • History of other malignancies with exception of: - in-situ carcinoma of the cervix or non-melanomatous skin cancer which have received curative therapy - cancer treated =5 years previously and considered as cured. • Patients with a known history of HIV seropositivity. • Patients with other concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled infection, ongoing chronic infection likely to worsen with inhibition of cellular immunity (e.g. chronic viral hepatitis, tuberculosis), uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within six months, active bleeding diathesis) • Patients with = grade 3 laboratory abnormalities (excluding hyperlipidemia) • Known hypersensitivity to everolimus or sirolimus (rapamycin), to letrozole or lactose (contained in formulations of RAD001 and Femara) • Patients with a history of noncompliance to medical regimens. • Patients unwilling to or unable to comply with the protocol. • Patients who received any other investigational drugs within the preceding 30 days. • 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 from randomization
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate superior efficacy of the combination therapy of RAD001 10mg daily plus letrozole 2.5 mg daily versus the combination of placebo plus letrozole 2.5 mg daily in postmenopausal women with metastatic or locally recurrent hormone receptor positive breast cancer based on Progression Free Survival (PFS).;Secondary Objective: To focus the demonstration of superior efficacy of the combination therapy on a subpopulation of patients thought to specifically benefit from the combination. This objective is dependent on the identification of a subpopulation having greater benefit from the combination treatment, based on intratumoral molecular characteristics, independently of the data from this study, and prior to the first interim analysis. To compare the two treatment arms with regard to the following secondary endpoints: Time To Progression, overall response rate, overall survival, safety and • to correlate specific molecular characteristics of the tumor with clinical outcome of the therapy • to investigate relationships between PK parameters of RAD001 and clinical endpoints, when combined with letrozole. • to investigate whether the genetic characteristics inherent to the individual are predictive of response to treatment, susceptibility to adverse events or drug-drug interactions. ;Primary end point(s): Progression Free Survival | — |
Countries
United Kingdom
Outcome results
None listed