E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with high risk of relapse, ER+ and HER2- primary non-metastatic breast cancer who remain disease-free. |
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E.1.1.1 | Medical condition in easily understood language |
Non-metastatic breast cancer. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 main objective of this trial is to evaluate the benefit of adding 2 years everolimus treatment to standard adjuvant endocrine treatments in patients who remain free of disease, with high risk of relapse. |
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E.2.2 | Secondary objectives of the trial |
1 - efficacy
2 - toxicity
3 - biology
4 - quality of life sub-studies
5 - EFS and DMFS in low risk patients (according to the EPClin score).
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biology and Quality of life |
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E.3 | Principal inclusion criteria |
1.Female ≥ 18 years of age,
2.Histologically proven invasive unilateral or bilateral breast cancer (regardless of the morphological type),
3.Any T, M0
4. Patient with high risk of relapse according to one of the conditions below:
- at least 4 positive lymph nodes if the patient had primary surgery
- or at least 1 positive lymph node if surgery was conducted after neo adjuvant chemotherapy or hormone therapy of at least 3 months duration
- or 1-3 positive lymph nodes (pN1a, b, c) at primary surgery AND EPClin score ≥ 3.32867
Note: Access to primary tumor for patients with 1-3 node positive is mandatory. Patient with EPClin score < 3.32867 will not be randomized, but will be followed yearly during 10 years.
5.ER+ and HER2 negative : Hormone receptor positive is defined as any staining on the primary tumor, HER2 negativity is defined as IHC 0-1+, or [IHC 2+ and FISH or CISH non amplified]
6.Primary tumor completely resected (deep margins and overlying skin involvement allowed if fully resected)
7.Patients who will begin an adjuvant hormone therapy or have received a maximum of 4 years of adjuvant hormone therapy. Hormone therapy could be either tamoxifen +/- LH-RH agonists, letrozole, anastrozole or exemestane.
8.No clinically or radiologically detectable metastases at time of inclusion.
9.WHO Performance status (ECOG) of 0 or 1.
10.Adequate hematological function (neutrophil count ≥ 2x109/l, platelet count ≥ 100x 109/l)
11.Adequate hepatic function: AST and ALT ≤ 2.5 ULN, alkaline phosphatases ≤ 2.5 ULN, total bilirubin ≤ 2 ULN.
12.Adequate renal function: serum creatinine ≤ 1.5 ULN.
13.Signed written informed consent.
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E.4 | Principal exclusion criteria |
1.Any local or regional recurrence metastatic disease.
2.Any clinical or radiological suspicion of malignant or pre-malignant disease in the contralateral breast.
3.Patients with pN1mi as sole nodal involvement
4.Previous cancer (excepted basal cell carcinoma of the skin or in situ carcinoma of the cervix) in the preceding 5 years, including invasive controlateral breast cancer.
5.Patient already included in another ongoing therapeutic trial involving an unlicensed drug for which follow-up is required.
6.Patient who is pregnant or breast-feeding. Adequate birth control measures should be taken during study treatment phase.
7.Patient with significantly impaired lung function (e.g. Chronic Obstructive Pulmonary Disease, respiratory insufficiency, Interstitial Lung Disease)
8.Positive serology for HIV infection or hepatitis C.
9.Chronic carrier of HBV (positive Antigen HbsAg positive in the blood)
10.Patient with chronic infection
11.Uncontrolled diabetes defined as glycated haemoglobin >7%.
12.Uncontrolled hypercholesterolemia (cholesterol >300 mg/dl under adequate therapy).
13.Known hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
14. Patient with other concurrent severe and/or uncontrolled medical disease or infection which could compromise participation in the study (e.g. patient who regularly require systemic steroids to control co-morbid disease).
15. Patient with any psychological, familial, social or geographical condition which could potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Disease free survival rate (DFS) after randomization (disease is defined as a local, regional or metastatic relapse, a contralateral breast cancer, or a death of any cause). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Using an inclusion period of 3 years and a minimum follow-up duration of 2 years for the last included patient, (which correspond to 5 years study duration), 286 events would be observed at the time of the final analysis. |
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E.5.2 | Secondary end point(s) |
1. Efficacy :
- Overall survival rate (OS) for the whole population,
- DFS and OS for ER+ and PR+ subgroup
- DFS and OS for the remainder ER+/PR – subgroup
- EFS
- DMFS
- Secondary cancer
2. Toxicity
- CTC-AE scale version 4.0.
3. biological :
- Predictive value of mTOR activation markers on DFS: IHC analysis of primary tumor for pS6K and p4EBP.
- Other translational analyses linking cancer biology with outcomes
4. Others
- Quality of life sub-studies : QLQ C30
- EFS and DMFS in low risk patients (according to the EPClin score).
- Sociologic study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biology and quality of life |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 16 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 16 |