E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The study will evaluate the safety of everolimus in patients with advanced neuroendocrine tumors of gastrointestinal, lung or pancreatic origin. |
Lo studio valuterà la sicurezza di everolimus nei pazienti con tumori neuroendocrini di origine gastrointestinale, polmonare o pancreatica in stadio avanzato. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced neuroendocrine tumor of gastrointestinal, lung or pancreatic origin. |
Tumore neuroendocrino di origine gastrointestinale, polmonare o pancreatica in stadio avanzato. |
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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 | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052399 |
E.1.2 | Term | Neuroendocrine tumour |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate additional safety of everolimus in patients with advanced neuroendocrine tumors of gastrointestinal, lung or pancreatic origin. |
Valutare ulteriormente la sicurezza d’impiego di everolimus in pazienti con tumori neuroendocrini avanzati di origine gastrointestinale, polmonare o pancreatica. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate investigator-assessed best overall response in patients with advanced NETs of gastrointestinal, lung or pancreatic origin treated with everolimus; - To estimate investigator-assessed progression free survival (PFS); - To provide expanded access to everolimus in patients with advanced NETs of gastrointestinal, lung or pancreatic origin; - To assess disease related symptoms and changes in health related quality of life (HRQoL) over time in advanced neuroendocrine patients treated with everolimus. |
- Valutare la miglior risposta complessiva a giudizio dello sperimentatore in pazienti con tumori neuroendocrini avanzati di origine gastrointestinale, polmonare o pancreatica, trattati con everolimus; - Stimare la sopravvivenza libera da malattia (Progression Free Survival – PFS) a giudizio dello sperimentatore; - Fornire accesso allargato a everolimus in pazienti con tumori neuroendocrini avanzati di origine gastrointestinale, polmonare o pancreatica; - Valutare i sintomi correlati alla malattia e le variazioni nel tempo della qualità della vita (Health Related Quality of Life – HRQoL) in pazienti con tumori neuroendocrini avanzati trattati con everolimus. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years old; 2. Advanced (unresectable or metastatic) biopsy-proven neuroendocrine tumor of gastrointestinal, lung or pancreatic origin; 3. Performance Status 0-2 on the WHO scale; 4. Adequate bone marrow function as shown by: • ANC ≥ 1.5 x 109/L, • Platelets ≥ 100 x 109/L, • Hemoglobin >9 g/dL; 5. Adequate liver function as shown by: • Serum bilirubin ≤ 1.5 x ULN, • ALT and AST ≤ 2.5 x ULN. Patients with known liver metastases who have an AST and ALT ≤ 5 x ULN, • INR < 1.3 (INR < 3 in patients treated with anticoagulants); 6. Adequate renal function as shown by: serum creatinine ≤ 1.5 x ULN; 7. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN; 8. Written informed consent obtained before any trial related activity and according to local guidelines. |
1. Età ≥ 18 anni; 2. Tumore neuroendocrino in fase avanzata (inoperabile o metastatico) di origine gastrointestinale, polmonare o pancreatica, confermato mediante biopsia; 3. WHO Performance Status ≤2; 4. Adeguata funzionalità del midollo osseo, dimostrata da: o ANC (conta assoluta dei neutrofili) ≥ 1.5 x 109/L, o Piastrine ≥ 100x 109/L, o Emoglobina > 9 g/dL; 5. Adeguata funzionalità epatica, documentata da: o Bilirubina totale ≤ 1.5 x ULN, o ALT e AST ≤ 2.5 x ULN; (≤ 5 x ULN in pazienti con metastasi epatiche note), o INR < 1.3; (< 3 in pazienti trattati con anticoagulanti); 6. Adeguata funzionalità renale, documentata da valori di creatinina sierica ≤ 1.5 x ULN; 7. Colesterolemia a digiuno ≤ 300 mg/dL o ≤ 7.75 mmol/L e trigliceridi a digiuno ≤ 2.5 x ULN; 8. Pazienti che hanno firmato il consenso informato scritto ottenuto prima dell’effettuazione di qualsiasi procedura relativa allo studio e secondo le linee guida locali. |
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E.4 | Principal exclusion criteria |
1. Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma are not eligible; 2. Cytotoxic chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to enrollment; 3. Hepatic artery embolization within the last 2 months or cryoablation or radiofrequency ablation of hepatic metastasis within 2 months of enrollment; 4. Prior therapy with mTOR inhibitors (for example sirolimus, temsirolimus, everolimus); 5. Patients with a known hypersensitivity to everolimus or other rapamycin analogs (sirolimus, temsirolimus), or to its excipients; 6. Patients receiving chronic treatment with immunosuppressives; 7. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 x ULN; 8. Patients who have any severe and/or uncontrolled medical conditions such as: • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to enrollment, serious uncontrolled cardiac arrhythmia, • active or uncontrolled severe infection, • Patients with a history of invasive fungal infections, • severe hepatic impairment (Child-Pugh class C), • severely impaired lung function; 9. Active bleeding diathesis; 10. Patients with a known history of HIV seropositivity. Screening for HIV infection at baseline is not required; 11. No other prior or concurrent malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for ≥ 3 years; 12. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry. Note: Patients must have recovered from the acute effects of surgery prior to enrollment; 13. Female patients who are pregnant or nursing (lactating);14. Adults of reproductive potential who are not using effective birth control methods. Adequate contraceptives must be used throughout the trial and for 8 weeks after last study drug administration in female patients. Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to first administration of study drug; 15. Patients unwilling to or unable to comply with the protocol. |
1. Pazienti affetti da carcinoma neuroendocrino scarsamente differenziato, carcinoma neuroendocrino di grado elevato, adenocarcinoide, carcinoide delle cellule caliciformi e carcinoma a piccole cellule; 2. Chemioterapia citotossica, immunoterapia o radioterapia nelle 4 settimane precedenti l’arruolamento; 3. Embolizzazione dell’arteria epatica nei 2 mesi precedenti o crioablazione o ablazione con radiofrequenza delle metastasi epatiche nei 2 mesi precedenti l’arruolamento; 4. Precedente terapia con inibitori di mTOR (ad esempio sirolimus, temsirolimus, everolimus); 5. Pazienti con ipersensibilità nota a everolimus o altri analoghi della rapamicina (sirolimus, temsirolimus) o dei suoi eccipienti; 6. Pazienti in trattamento cronico con immunosoppressori; 7. Diabete mellito non controllato definito da una glicemia a digiuno > 1.5 x ULN; 8. Pazienti affetti da patologia severa e/o non controllata, quali: o Angina pectoris instabile, insufficienza cardiaca congestizia cronica sintomatica, infarto del miocardio ≤6 mesi prima dell’arruolamento, aritmia cardiaca grave non controllata, o Infezione attiva grave o non controllata, o Pazienti con storia di infezioni fungine invasive, o Insufficienza epatica grave (Child-Pugh classe C), o Funzionalità polmonare gravemente compromessa; 9. Diatesi emorragica attiva; 10. Pazienti con nota sieropositività per HIV. Non è richiesto lo screening per l’infezione da HIV al basale; 11. Pazienti con anamnesi positiva per un’altra neoplasia non in trattamento da ≥ 3 anni, ad eccezione di: carcinoma cutaneo basocellulare o a cellule squamose o altro carcinoma in situ adeguatamente trattato; 12. Pazienti che hanno subito un intervento chirurgico maggiore (ad esempio intra-toracico, intra-addominale o intra-pelvico), biopsia aperta o ferita traumatica significativa nelle 4 settimane precedenti l’arruolamento per evitare complicazioni nella guarigione della ferita. Procedure minori e biopsie percutanee o il posizionamento di un dispositivo di accesso vascolare richiedono un intervallo di almeno 7 giorni prima dell’arruolamento; 13. Pazienti di sesso femminile in gravidanza o in corso di allattamento; 14. Adulti potenzialmente fertili che non utilizzino metodi contraccettivi efficaci. Le pazienti di sesso femminile devono utilizzare metodi contraccettivi adeguati per tutta la durata dello studio e per 8 settimane dopo l’ultima somministrazione del farmaco in studio; 15. Pazienti che non desiderano o non sono in grado di soddisfare i requisiti del protocollo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the safety of everolimus: grade 3 or 4 adverse events, serious adverse events, laboratory abnormalities of CTC grade 3 or 4. |
Valutazione del profilo di sicurezza di everolimus: eventi avversi di grado 3 e 4, eventi avversi seri, anomalie di laboratorio di grado CTC 3 o 4. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
15 months or until disease progression, unacceptable toxicity, death, discontinuation from the study for any other reason. |
15 mesi o fino a progressione di malattia, tossicità inaccettabile, decesso, interruzione dello studio per qualsiasi altro motivo. |
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E.5.2 | Secondary end point(s) |
- To evaluate investigator-assessed best overall response in patients with advanced NETs of gastrointestinal, lung or pancreatic origin treated with everolimus; - To estimate investigator-assessed progression free survival (PFS); - To provide expanded access to everolimus in patients with advanced NETs of gastrointestinal, lung or pancreatic origin; - To assess disease related symptoms and changes in health related quality of life (HRQoL) over time in advanced neuroendocrine patients treated with everolimus. |
- Valutare la miglior risposta complessiva a giudizio dello sperimentatore in pazienti con tumori neuroendocrini avanzati di origine gastrointestinale, polmonare o pancreatica, trattati con everolimus; - Stimare la sopravvivenza libera da malattia (Progression Free Survival – PFS) a giudizio dello sperimentatore; - Fornire accesso allargato a everolimus in pazienti con tumori neuroendocrini avanzati di origine gastrointestinale, polmonare o pancreatica; - Valutare i sintomi correlati alla malattia e le variazioni nel tempo della qualità della vita (Health Related Quality of Life – HRQoL) in pazienti con tumori neuroendocrini avanzati trattati con everolimus. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
15 months or until disease progression, unacceptable toxicity, death, discontinuation from the study for any other reason. |
15 mesi o fino a progressione di malattia, tossicità inaccettabile, decesso, interruzione dello studio per qualsiasi altro motivo. |
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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 | No |
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 | 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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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
| 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 | 21 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 103 |
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 | No |
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 |
Argentina |
Brazil |
Colombia |
Israel |
Korea, Republic of |
Lebanon |
Mexico |
Russian Federation |
Saudi Arabia |
South Africa |
Taiwan |
Thailand |
United Arab Emirates |
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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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The end of trial will be 30/05/2012 or until everolimus becomes commercially available for this indication in each participating country for this indication in each country, whichever occurs first. |
Lo studio si concluderà il 30/05/2012 o fino alla commercializzazione di everolimus per questa indicazione in ciascun Paese partecipante, a seconda di quale situazione si verifichi per prima. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 15 |
E.8.9.2 | In all countries concerned by the trial days | 0 |