| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with somatostatin receptor positive, well-differentiated G2 and G3, advanced GEP NETs |
| Pazienti con GEP-NET in stadio avanzato, positivi ai recettori della somatostatina, di grado 2 (G2) e 3 (G3) ben differenziati |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with tumors that have a specific target (GEP NET) for treatmentwith Lutathera |
| Pazienti con tumori che hanno un target specifico (GEP-NET) per il trattamento con Lutathera |
|
| 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 | 21.0 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077559 |
| E.1.2 | Term | Gastroenteropancreatic neuroendocrine tumour disease |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10077560 |
| E.1.2 | Term | Gastroenteropancreatic neuroendocrine tumor disease |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 demonstrate that Lutathera is superior to active comparator in delaying the time-to-first occurrence of progression or death (PFS) as first line treatment. |
| Dimostrare che Lutathera è superiore al comparatore attivo nel ritardare il tempo al primo evento di progressione o al decesso (PFS) come trattamento di prima linea. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of objective response
-To demonstrate the superiority of Lutathera, compared to active comparator, in terms of time to deterioration in selected QoL items/scales.
Other Secondary Objectives:
-To evaluate the efficacy of Lutathera, compared to active comparator, in keeping the disease under control
-To evaluate the efficacy of Lutathera, compared to active comparator, in terms of duration of response
-To evaluate the safety and tolerability of Lutathera
-To evaluate the effect of Lutathera on survival |
Obiettivi secondari principali:
- Dimostrare la superiorità di Lutathera, rispetto al comparatore attivo, in termini di risposta obiettiva
- Dimostrare la superiorità di Lutathera, rispetto al comparatore attivo, in termini di tempo al deterioramento in voci/scale selezionate di qualità della vita (QoL).
Altri obiettivi secondari:
- Valutare l’efficacia di Lutathera, rispetto al comparatore attivo, nel tenere sotto controllo la malattia
- Valutare l’efficacia di Lutathera, rispetto al comparatore attivo, in termini di durata della risposta
- Valutare la sicurezza e la tollerabilità di Lutathera
- Valutare l’effetto di Lutathera sulla sopravvivenza |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
2. Ki67 index =10 and = 55%.
3. Patients =15 years of age and a body weight of >40 kg at screening.
4. Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization:
[68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT imaging or [68Ga]-DOTA-TATE PET/CT imaging (e.g. NETSPOT®) or Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan® SPECT/CT).
5. The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
6. Karnofsky Performance Score (KPS) =60.
7. Presence of at least 1 measurable site of disease.
8. Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities. |
1. Presenza di tumore neuroendocrino gastro-entero-pancreatico (GEP-NET) metastatizzato o localmente avanzato, determinato come non operabile (intento terapeutico) all’esame istologico, di grado 2 o grado 3 ben differenziato, diagnosticato entro i 6 mesi precedenti allo screening.
2. Indice Ki67 =10 e =55%.
3. Pazienti =15 anni di età e peso corporeo >40 kg allo screening.
4. Espressione dei recettori della somatostatina su tutte le lesioni bersaglio, documentata mediante esami TAC/RM, valutata mediante le seguenti modalità di diagnostica per immagini dei recettori della somatostatina (SRI), entro i 3 mesi precedenti alla randomizzazione: diagnostica per immagini con tomografia a emissione di positroni (PET)/TAC [68Ga]-DOTA-TOC (per es. Somakit-TOC®) o PET/TAC [68Ga]-DOTA-TATE (per es. NETSPOT®) o scintigrafia dei recettori della somatostatina (SRS) con 111In-pentetreotide (tomografia a emissione di fotone singolo [SPECT]/TAC Octreoscan®).
5. La captazione del tumore osservata nelle lesioni bersaglio deve essere > alla normale captazione epatica osservata con immagini diagnostiche planari.
6. Punteggio ¿60 sulla scala di valutazione delle prestazioni di Karnofsky (KPS).
7. Presenza di almeno 1 sito di malattia misurabile.
8. I pazienti che hanno fornito un modulo di consenso informato firmato per partecipare allo studio, ottenuto prima di iniziare qualsiasi attività relativa al protocollo. |
|
| E.4 | Principal exclusion criteria |
1. Creatinine clearance <40 mL/min calculated by the Cockroft Gault method.
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x10^9/L (2000/mm3); platelets <75x10^9/L (75x10^3/mm3).
3. Total bilirubin >3 x ULN.
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 6 months after study drug discontinuation.
7. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
8. Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
9. Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than the therapy offered in the study, based on patient and disease characteristics.
10. Any previous therapy with Interferons, Everolimus (mTOR- inhibitors), chemotherapy or other systemic therapies administered for more than 1 month and within 12 weeks prior to randomization in the study.
11. Any previous radioembolization, chemoembolization and radiofrequency ablation.
12. Any surgery within 12 weeks prior to randomization in the study.
13. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
14. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization, preferably via gated equilibrium radionuclide ventriculography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be >40% before randomization.
15. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
16. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
17. Hyperkaleamia >6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
18. Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (eg octreotide long-acting), which cannot be interrupted for at least 6 weeks before the
administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
19. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
20. Prior external beam radiation therapy to more than 25% of the bone marrow.
21. Current spontaneous urinary incontinence.
22. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
23. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
24. Patients with known intolerance or hypersensitivity to any somatostatin analogs
25. Patients who have participated in any clinical study/received any investigational agent within the last 30 days. |
1. Clearance della creatinina <40 ml/min calcolata con il metodo di Cockcroft-Gault.
2. Concentrazione di emoglobina (Hb) <5,0 mmol/l (<8,0 g/dl); leucociti (WBC) <2x109/l (2000/mm3); piastrine <75x109/l (75x103/mm3).
3. Bilirubina totale >3 x limite superiore della norma (ULN).
4. Albumina sierica <3,0 g/dl, a meno che il tempo di protrombina non rientri nell’intervallo di normalità.
5. Gravidanza o allattamento.
6. Le donne in età fertile, definite come tutte le donne fisiologicamente in grado di intraprendere una gravidanza, non potranno partecipare a questo studio, A MENO CHE non utilizzino metodi contraccettivi altamente efficaci per tutta la durata dello studio e per i 6 mesi successivi all’interruzione del farmaco dello studio.
7. Terapia recettoriale con peptidi radiomarcati (PRRT) in qualsiasi momento prima della randomizzazione nello studio.
8. Progressione documentata secondo i criteri RECIST con trattamenti precedenti per l’attuale GEP-NET in qualsiasi momento prima della randomizzazione.
9. Pazienti per i quali, secondo l’opinione dello sperimentatore, sono considerate più adatte altre opzioni terapeutiche (per es. chemio-, terapia mirata) rispetto alla terapia proposta nello studio, in base alle caratteristiche del paziente e della malattia.
10. Qualsiasi precedente terapia con interferoni, everolimus (inibitori del bersaglio della rapamicina nei mammiferi [mTOR]), chemioterapia o altre terapie sistemiche somministrate per più di 1 mese ed entro le 12 settimane precedenti alla randomizzazione nello studio.
11. Qualsiasi precedente radioembolizzazione, chemioembolizzazione e ablazione con radiofrequenza.
12. Qualsiasi intervento chirurgico subito entro le 12 settimane precedenti alla randomizzazione nello studio.
13. Metastasi cerebrali note, a meno che non siano state trattate e stabilizzate da almeno 24 settimane, prima dello screening nello studio. I pazienti con anamnesi di metastasi cerebrali devono essersi sottoposti a una TAC cerebrale con mezzo di contrasto per la documentazione di malattia stabile prima della randomizzazione nello studio.
14. Insufficienza cardiaca congestizia non controllata (stadi II, III, IV della classificazione della New York Heart Association [NYHA]). I pazienti con anamnesi di insufficienza cardiaca congestizia che non violano questo criterio di esclusione saranno sottoposti a una valutazione della frazione di eiezione cardiaca prima della randomizzazione, preferibilmente tramite ventricolografia con radionuclidi all’equilibrio. I risultati di una precedente valutazione (risalente a non più di 30 giorni prima della randomizzazione) possono sostituire la valutazione, a discrezione dello sperimentatore, se non si osserva un peggioramento clinico. La misurazione della frazione di eiezione cardiaca del paziente in questi pazienti deve essere >40% prima della randomizzazione.
15. Intervallo QT corretto con formula di Fridericia (QTcF) >470 msec per soggetti di sesso femminile e QTcF >450 msec per soggetti di sesso maschile o sindrome congenita del QT lungo.
16. Diabete mellito incontrollato, definito da livelli di glicemia a digiuno >2 ULN.
17. Iperkaliemia >6,0 mmol/l (di grado 3 secondo i Criteri terminologici comuni per gli eventi avversi [CTCAE]) non corretta prima dell’arruolamento nello studio.
Per i criteri da 18 a 25 si veda la sezione in inglese. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS): Time from randomization to the first line progression |
| Sopravvivenza libera da progressione (PFS): tempo trascorso dalla randomizzazione alla prima progressione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 99 PFS events |
| Dopo 99 eventi eventi di progressione di malattia o decesso valutabili e confermati a livello centrale (PFS) |
|
| E.5.2 | Secondary end point(s) |
-ORR: rate of complete and partial responses (CR, PR)
-Time to decline (TTD) by 10 points from baseline in the total score for health status as measured by the EORTC QLQ-G.I.NET21 questionnaire, EORTC QLQC30 questionnaire:
global health status (TTD)-diarrhea (TTD)-fatigue, (TTD)- pain (TTD). |
- ORR: tempistica delle risposte complete o parziali (CR, PR)
- Tempo di diminuzione (TTD) di 10 punti dalla baseline nel punteggio totale per lo stato di salute misurato tramite i questionari EORTC QLQ-G.I.NET21 , EORTC QLQC30:
stato globale di salute (TTD)-diarrea (TTD)-stanchezza, (TTD)- dolore (TTD). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of treatment phase or after discontinuation |
| Alla fine della fase di trattamento o dopo l'interruzione del trattamento. |
|
| 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 | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Sandostatin LAR Depot |
| Sandostatin LAR Depot |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Brazil |
| Canada |
| China |
| Korea, Republic of |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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
|
| The End of Study is after 4 years have elapsed from the randomization of the last patient. |
| La fine dello studio si verificherà una volta trascorsi 4 anni dalla randomizzazione dell’ultimo paziente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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