E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Estrogen receptor positive locally advanced or metastatic breast cancer in postmenopausal women |
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E.1.1.1 | Medical condition in easily understood language |
Estrogen receptor positive locally advanced or metastatic breast cancer in postmenopausal women |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070575 |
E.1.2 | Term | Estrogen receptor positive 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 |
to evaluate safety of everolimus (RAD001) in postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer that is refractory to NSAIs |
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E.2.2 | Secondary objectives of the trial |
- to evaluate adverse events grade 3 and 4 in the routine practice
- to explore the tolerability of the concomitant treatment of zoledronic acid RTU (Ready To Use) formulation in patients who will receive this treatment according to the clinical practice |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
2.Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
3.Postmenopausal women. Postmenopausal status is defined either by:
•Age ≥ 55 years and one year or more of amenorrhea
•Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml
•Surgical menopause with bilateral oophorectomy
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
4.Disease refractory to NSAI, defined as:
a. Recurrence while on or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or
b. Progression while on or within one month of end of letrozole or anastrozole treatment for advanced BC
5.Adequate bone marrow and coagulation function as shown by:
•Absolute neutrophil count (ANC) ≥ 1.5 109/L
•Platelets ≥ 100 ×109/L
•Hemoglobin (Hgb) ≥ 9.0 g/dL
•INR ≤ 2
6.Adequate liver function as shown by:
•Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN (or ≤ 5 if hepatic metastases are present)
•Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert Syndrome)
7.Adequate renal function as shown by:
•Serum creatinine ≤ 1.5 × ULN
8.Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN |
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E.4 | Principal exclusion criteria |
1.HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
2.Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting providing patient remained disease-free for at least one year following completion.
3.Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
4.Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:
Topical applications, inhaled sprays, eye drops or local injections are allowed.
Patients on stable low dose of corticosteroids for at least two weeks before enrollment are allowed in case of treatment of brain metastases .
5.Bilateral diffuse lymphangitic carcinomatosis or metastasis of the lung as the only manifestation of disease (>50% of lung involvement), evidence of metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan.
6.Patients with a known history of HIV seropositivity.
7.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)
8.Any severe and / or uncontrolled medical conditions such as:
•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
•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.
9.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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
frequency of adverse events and number of laboratory values that are new or worsening |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events: continuously, up to 28 days after last treatment
Laboratory values: continuously or as frequently as clinically indicated |
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E.5.2 | Secondary end point(s) |
- frequency of adverse events that is recorded as Grade 3 or 4 or as Serious Adverse Event
- frequency of adverse events of any grade in the group of patients who have received concomitant treatment with zoledronic acid RTU formulation, administered according to clinical practice |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuously, up to 28 days after the last treatment |
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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 | No |
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 | 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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 500 |
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 | No |
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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LPLV (last patient last visit) |
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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 | 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 | 9 |