E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072737 |
E.1.2 | Term | Advanced breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
Analyze the value of pneumoproteins, immunological parameters, everolimus exposure, pulmonary function tests, distinct radiological patterns, baseline patient characteristics and the development of skin toxicity or mucositis for the prediction of the development and severity of everolimus-induced interstitial lung disease. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- Determine whether a decline in pulmonary function test or the occurrence of new radiological pulmonary abnormalities is preceded by an increase in the level of pneumoproteins
- Investigate the pathophysiology of everolimus-induced ILD, skin toxicity and oral mucositis
- Describe the outcomes of a standardized treatment strategy for everolimus-induced ILD
- Correlate the development and grade of everolimus-induced ILD, skin toxicity and oral mucositis with everolimus exposure (AUC) and outcome (PFS)
- Determine the type and frequency of lung parenchymal changes and its discriminative power from other (not drug-related) lung changes
- Determine the impact of radiological interreader variability on patient management |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
- Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
- Postmenopausal women. Postmenopausal status is defined either by:
o Age ≥ 55 years and one year or more of amenorrhea
o Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml
o Surgical menopause with bilateral oophorectomy
- Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment.
- Progression following a non-steroidal aromatase inhibitor
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
- Adequate renal function: calculated creatinine clearance (as estimated by GFR using the MDRD formula) is MDRD ≥ 30ml/min/1.73m2
- Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)
- Patient is willing and able to sign the Informed Consent Form prior to screening evaluations |
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E.4 | Principal exclusion criteria |
- HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
- Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting.
- Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
- Patients with a known history of HIV seropositivity.
- Any severe and / or uncontrolled medical conditions such as:
o Unstable angina pectoris, serious uncontrolled cardiac arrhythmia
o Patients with severe hepatic impairment (Child-Pugh A/B/C)
o Uncontrolled diabetes mellitus
o Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
- 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). Only patients at higher risk for hepatitis B or C will be tested.
- Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment
- History of non-compliance to medical regimens
- Patients unwilling to or unable to comply with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Find the correlation between:
- baseline patient characteristics (smoking, preexistent lung disease)
- pneumoproteins; KL-6, surfactant protein A, surfactant protein D, CC16, CCL18, YKL-40, LDH and CA 15.3 (absolute number and difference from baseline)
- immunologic parameters (i.e. T-cell activation status and cytokine profile, DC subtyping, immune checkpoint proteins)
- everolimus exposure (AUC on day 14 and mini-AUC at moment of toxicity)
- pulmonary function tests: spirometry including FVC and DLCO adjusted for hemoglobin (absolute number and difference from baseline)
- four distinct radiological patterns of 1.0mm CT slices of the lungs (as described in paragraph 6.2.7, page 30)
- the development and grade of everolimus-induced skin toxicity and oral mucositis
and the development and grade of everolimus-induced ILD, using univariate and multivariate analysis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Analyze the temporal relationship between a decrease in pulmonary function or the occurrence of new radiological pulmonary abnormalities and an increase in the level of pneumoproteins
- Investigate which immunological changes (cytokines, T-cells, dendritic cells) are observed in peripheral blood, skin biopsies and bronchoalveolar lavage of patients with everolimus-induced toxicity
- Assess the duration and severity of ILD when patients are treated according to a standardized diagnostic and treatment strategy
- Define the correlation between everolimus induced ILD on the one hand and everolimus exposure (as per AUC0-24h) on day 14) and outcome (as per PFS) on the other hand
- Determine the type and frequency of lung parenchymal changes and its discriminative power from other (not drug-related) lung changes
- Describe the quantity and quality of differences in judgment of HRCT images between a local and a central radiologist |
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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 | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.3 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |