E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable, locally advanced or metastatic G3 Neuroendocrine Neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin. |
Neoplasia neuroendocrina (NNE) G3 irresecable, localmente avanzada o metastásica del tracto gastroenteropancreático (GEP) o de origen desconocido. |
|
E.1.1.1 | Medical condition in easily understood language |
Neuroendocrine tumor of the gastroenteropancreatic tract or of unknown origin |
Tumor neuroendocrino del tracto gastroenteropancreatico o de origen desconocido |
|
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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067517 |
E.1.2 | Term | Pancreatic 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 | LLT |
E.1.2 | Classification code | 10067518 |
E.1.2 | Term | Pancreatic neuroendocrine tumor |
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 | 10068909 |
E.1.2 | Term | Pancreatic neuroendocrine tumour metastatic |
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 | 10068916 |
E.1.2 | Term | Pancreatic neuroendocrine tumor metastatic |
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 | 10071542 |
E.1.2 | Term | Neuroendocrine carcinoma metastatic |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the overall survival patients with advanced G3 NENs treated with nivolumab + platinum-based chemotherapy. |
Determinar la tasa de supervivencia global de pacientes con NNE G3 avanzados con nivolumab + quimioterapia basada en platino. |
|
E.2.2 | Secondary objectives of the trial |
- To determine other efficacy outcomes of nivolumab + platinum-based chemotherapy in patients with advanced G3 NENs. - To evaluate the safety and tolerability of nivolumab + platinum-based chemotherapy in this patient population. - To evaluate biochemical response as predictive biomarker of efficacy of nivolumab + chemotherapy in this patient population. - To explore potential predictive and prognostic biomarkers. |
- Determinar otros criterios de valoración de la eficacia de nivolumab + quimioterapia basada en platino en pacientes con NNE G3 avanzados. - Evaluar la seguridad y tolerabilidad de nivolumab + quimioterapia basada en platino en esta población de pacientes. - Evaluar la respuesta bioquímica como biomarcador predictivo de la eficacia de nivolumab + quimioterapia en esta población de pacientes. - Explorar posibles biomarcadores predictivos y pronósticos. |
|
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 |
Biomarkers study |
Estudio de biomarcadores |
|
E.3 | Principal inclusion criteria |
- Histologically confirmed G3 NENs originated in the gastroenteropancreatic tract (WHO 2015/2019 classification). Patients with a G3 NEN of unknown primary will also be eligible for this trial. - Ki-67 >20% or mitotic rate > 20 per 10 HPF. - Metastatic or locally advanced unresectable disease not amenable to treatment with curative intent. - No prior systemic treatment for advanced disease nor as adjuvant therapy permitted. - Availability of fresh or archive formalin-fixed, paraffin-embedded tumor tissue for biomarker assessment. - Patients must have clinically and/or radiographically documented measurable disease. - Adequate organ function as defined by the following criteria absolute neutrophil count (ANC) ≥1500 cells/mm3; platelets ≥100,000 cells/mm3; hemoglobin ≥9.0 g/dL; AST and ALT ≤2.5 x upper limit of normal (ULN); in patients with liver metastases AST and ALT ≤5.0 x ULN; total bilirubin ≤1.5 x ULN; serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min. - ECOG performance status of 0-2. |
- NNE G3 gastroenteropancreático (clasificación de la OMS 2015/2019) histológicamente confirmado. También serán elegibles para este estudio los pacientes con un NNE G3 de origen desconocido. - Ki-67 >20 % o índice mitótico >20 por 10 HPF. - Enfermedad irresecable metastásica o localmente avanzada no susceptible de tratamiento con intención curativa. - No se permite el tratamiento sistémico previo para la enfermedad avanzada ni como tratamiento adyuvante. - Disponibilidad de tejido tumoral recién reciente o de archivo fijado en formol e incluido en parafina para la evaluación de biomarcadores. - Los pacientes deben tener enfermedad cuantificable clínicamente y/o radiográficamente documentada. - Función orgánica aceptable, definida por los criterios siguientes: Recuento absoluto de neutrófilos (RAN) ≥1500 células/mm3; Plaquetas ≥100 000 células/mm3; Hemoglobina ≥9,0 g/dl; AST y ALT ≤2,5 veces el límite superior de la normalidad (LSN); en pacientes con metástasis hepáticas, AST y ALT ≤5,0 x LSN; Bilirrubina total ≤1,5 veces el LSN. Creatinina sérica ≤1,5 veces el LSN o aclaramiento de creatinina calculado ≥60 ml/min. - Estado funcional del ECOG de 0-2. |
|
E.4 | Principal exclusion criteria |
- The following endocrine tumor types may not be included: paraganglioma, adrenal, thyroid parathyroid or pituitary endocrine tumors. Large or small cell lung neuroendocrine carcinoma of the lung will also be excluded. - Prior therapy with any immune checkpoint inhibitor. - Prior organ transplantation, including allogeneic stem-cell transplantation. - Systemic chronic steroid therapy (> 10 mg/day prednisone or equivalent) or other immunosuppressive agents or use of any investigational drug within 28 days before the start of trial treatment. - Known history of positive testing for Human Immunodeficiency Virus (HIV) infection, known history of positive tests for Hepatitis B virus surface antigen (HBVsAg) or Hepatitis C ribonucleic acid (HCV RNA) indicating acute or chronic infection or other significant acute or chronic infections requiring medication at study entry. |
- No se pueden incluir los siguientes tipos de tumor endocrino: paraganglioma, suprarrenal, tiroides o paratiroides o tumores endocrinos hipofisarios. También se excluirá el carcinoma neuroendocrino pulmonar de células grandes o pequeñas. - Tratamiento previo con cualquier inhibidor de (checkpoint) punto de control del sistema inmunitario. - Antecedente de trasplante de órganos, incluido alotrasplante de células madre. - Tratamiento sistémico crónico con corticosteroides (>10 mg/día de prednisona o equivalente) u otros inmunosupresores o uso de un fármaco en investigación en los 28 días anteriores al inicio del tratamiento del estudio. - Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH), antecedentes conocidos de pruebas positivas para el antígeno de superficie del virus de la hepatitis B (HBVsAg) o de ácido ribonucleico de la hepatitis C (ARN del VHC) que indica una infección aguda o crónica, u otras infecciones agudas o crónicas significativas que requieren medicación en el momento de la inclusión en el estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overal survival rate |
Tasa de supervivencia global |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 year after start of treatment |
1 año tras el inicio del tratamiento en estudio |
|
E.5.2 | Secondary end point(s) |
- Overall response rate (ORR) - Duration of response (DoR) - Progression-free survival (PFS) - Overall survival (OS) - Incidence of adverse events (AEs), severe AEs and selected AEs. - Chromogranin A and enolase values and their association with ORR, PFS and OS. - Mutational burden, gene expression signature, soluble factors and other molecular markers in peripheral blood and their association with clinical outcomes. - |
- Duración de la respuesta - Supervivencia libre de progresión (SLP) - Supervivencia Global - Incidencia de acontecimientos adversos (AA), AA graves (AAG) y AA seleccionados. - Valores de cromogranina A y enolasa y su asociación con la TRG, la SLP y la SG. - Carga mutacional, distintivo de expresión génica, factores solubles y otros marcadores moleculares en sangre periférica y su asociación con los resultados clínicos. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of follow up |
Fin de seguimiento |
|
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 |
Evaluation of biomarkers' impact on clinical outcome |
Evaluación del impacto de los biomarcadores en la evolución clínica |
|
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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
| 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 | 12 |
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
|
Last subject's last visit |
Última visita del último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |