E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic treatment for breast cancer given when the primary tumors are still present in situ within the breast can result in large tumors being down-staged, which can allow for more conservative surgery. Letrozole (Femara) has shown to be superior to tamoxifen in this setting but with scope left for improvement. This study will investigate the additive effect that RAD001 (everolimus), can bring to therapy with letrozole in this setting. |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• the added efficacy obtained by the association of RAD001 with letrozole as preoperative therapy of primary, hormone-receptor positive breast cancer in postmenopausal women as shown by increased clinical tumor response rates • the pretreatment molecular characteristics of tumor or their modifications early in the treatment as being predictive of clinical tumor response.
|
|
E.2.2 | Secondary objectives of the trial |
To compare the safety and tolerability of the treatment regimens. To investigate whether a reduction in tumor volume is correlated to changes in biological marker expression. To compare the number of patients that have breast-conserving surgery rather than mastectomy in the two groups after 4 months of treatment. To compare the frequency of complete pathological response achieved in the two groups after 4 months of treatment. To investigate whether co-administration of RAD001 10mg/day with letrozole 2.5 mg/day does influence letrozole pharmacokinetics and whether exposure to RAD001 is altered in the presence of letrozole, compared to historical exposure data. To investigate tumor-specific mutations and compare gene expression changes in tumor cells with blood cells and plasma for biomarker development. To investigate whether the genetic characteristics inherent to the individual are predictive of response to treatment, susceptibility to adverse events or drug-drug interactions. |
|
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
• Adult female patients (≥18 years old) • Histologically-confirmed diagnosis of invasive breast cancer, previously untreated (patients who have been treated for cancer of the contralateral breast can be included if there is at least a 2 year time interval from last systemic treatment for breast cancer before randomization into this study) • 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 • < 55 years of age without menses for the last 5 years or • < 55 years of age and has not had menses for at least the last 12 months (but has had menses in the last 5 years) and has postmenopausal levels of FSH (according to the postmenopausal range of the individual laboratory, and performed at least four weeks after stopping HRT/oral contraceptives) 3. Women without an intact uterus and • ≥ 55 years of age or • < 55 years of age and postmenopausal levels of FSH (according to the postmenopausal range of the individual laboratory, and performed at least four weeks after stopping HRT/oral contraceptives) • Candidates for mastectomy or breast-conserving surgery • Primary tumor of above 2 cm diameter, measured by imaging • Primary tumor is ER positive, defined as: ≥ 10% of the nuclei in the invasive component of the tumor stain positive after immunostaining (analyzed in local laboratory) • Clinical Stage M0 (bone scan, chest X-ray and abdominal CT scan or liver ultrasound required at screening to exclude metastatic disease) • WHO performance status ≤ 1 • Adequate bone marrow function as shown by: WBC ≥3.5 x 10 9/L, ANC ≥ 1.5 x 10 9/L, Platelets ≥ LLN, Hb >10g/dL • Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN, albumin ≥ 3 g/dl, serum transaminases activity ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN • Normal renal function (serum creatinine ≤ 1.5 x ULN, BUN ≤ 1.5 x ULN) • 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 information. |
|
E.4 | Principal exclusion criteria |
• Patients with multifocal invasive tumors • Patients with bilateral or inflammatory breast cancer (a bilateral mammography is required at screening visit) • Patients receiving concomitant anti-cancer treatments such as chemotherapy, immunotherapy/biological response modifiers (BRMs), endocrine therapy (including steroids), and radiotherapy. Patients who have received hormone replacement therapy will NOT be excluded, provided that HRT is discontinued at least 2 weeks prior to entry into the study (i.e. 2 weeks prior to screening assessments). • Known hypersensitivity to everolimus or sirolimus (rapamycin), to letrozole or lactose (contained in formulations of RAD001 and letrozole) • ≥ grade 3 hypercholesterolemia/ hypertriglyceridemia or ≥ grade 2 hypercholesterolemia/ hypertriglyceridemia with history of coronary artery disease (despite lipid-lowering treatment if given) • Patients with an uncontrolled infection • Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (i.e., uncontrolled diabetes mellitus, uncontrolled cardiac disease (unstable angina), uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within six months, chronic liver or renal disease, active upper GI tract ulceration) • Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. • Patients with a history of noncompliance to medical regimens • Patients unwilling or unable to comply with the protocol (especially: 15-day biopsy, necessity to undergo breast surgery despite a clinical complete response) • Patients who received any other investigational drugs within the 30 days prior to the screening visit • 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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Clinical tumour response rate |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |