| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| METASTATIC GRADE 3 POORLY DIFFERENTIATED NEUROENDOCRINE CARCINOMA OF GASTRO ENTERO PANCREATIC AND UNKNOWN PRIMARY |
| Carcinome neuroendocrine peu différencié de grade 3 ou MINEN avec composante de carcinome neuroendocrine peu différencié de grade 3 Primitif d’origine gastro-entero-pancréatique ou inconnue |
|
| E.1.1.1 | Medical condition in easily understood language |
| METASTATIC NEUROENDOCRINE CARCINOMA |
| Carcinome neuroendocrine métastatique |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 compare the progression-free survival (PFS) with mFOLFIRINOX regimen versus platinum - etoposide regimen according to the investigator using RECIST v1.1 criteria. |
| Comparer la survie sans progression (SSP) entre mFOLFIRINOX et platine – étoposide évaluée par l’investigateur selon les critères RECIST 1.1. |
|
| E.2.2 | Secondary objectives of the trial |
PFS according to the centralized review (RECIST v1.1 criteria)
Best objective response rate (ORR)
Median overall survival (OS)
Safety according to NCI CTC V4.0
Dose-reductions
Quality of life assessed by EORTC QLQ-C30 and EQ-5D-5L
To establish a molecular profile within 2 months after tumor sample submission for each patient enrolled in the study and to provide a molecular tumor board report to the treating physician.
Frequency of Rb loss in G3 NEC irrespective of the SC or LC subtype
Correlation of ORR, PFS and OS under both chemotherapy regimens with molecular alterations (Rb, TP53, MSH2…) |
SSP selon la relecture centralisée (critères RECIST v1.1)
Taux de réponse objective (TRO)
Survie globale (SG)
Evènements indésirables selon le NCI CTC V4.0
Dose intensité - réductions de dose
Qualité de vie évaluée par les questionnaires EORTC, QLQ-C30 et EQ-5D-5L
Etablir un profil moléculaire dans les 2 mois après l’envoi de l’échantillon de la tumeur pour chaque patient inclus dans l’étude et fournir un compte-rendu de RCP moléculaire à l’investigateur prenant en charge le patient.
Pourcentage de perte d’expression de Rb (indépendamment du sous-groupe petites cellules ou grandes cellules)
Corrélation entre TRO, SSP et SG et les altérations moléculaires (Rb, TP53, MSH2…) dans les deux bras de traitement |
|
| 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 |
FOLFIRINEC study is coupled with the establishment of a molecular profile by next generation sequencing (NGS) and immunohistochemistry, which will be discussed in a dedicated molecular tumor board. The molecular report will be sent to the investigator, during the trial, within 2 months after tumor sample submission. This molecular profile will also be used to explore for predictive biomarkers of response to chemotherapy.
Blood samples will be collected for ctDNA analysis.
|
| L’étude FOLFIRINEC est couplée à la réalisation d’un profil moléculaire de chaque tumeur par NGS, et immunohistochimie. Ce profil moléculaire fera l’objet d’une discussion en RCP moléculaire. Le compte-rendu de RCP moléculaire sera envoyé à l’investigateur durant l’essai clinique environ deux mois après réception du bloc tumoral. Ce profil moléculaire permettra aussi d’explorer les biomarqueurs de réponse à la chimiothérapie. Des échantillons sanguins seront également collectés pour l’analyse de l’AND tumoral circulant |
|
| E.3 | Principal inclusion criteria |
•Grade 3 neuroendocrine carcinoma or high grade MiNEN with a grade 3 poorly differentiated neuroendocrine carcinoma component ≥30% of gastro-entero-pancreatic or unknown primary
•Poorly differentiated
•Small cell or large cell or non-small cell or non- typeable
•Metastatic disease
•First-line, no prior therapy for metastatic disease, no prior use of carboplatin, oxaliplatin, cisplatin, etoposide, irinotecan and 5-fluorouracile
•At least one measurable lesion as assessed by CT-scan or MRI according to RECIST 1.1 guidelines
•Available tumor block
•ANC ≥ 1.5x109/l, platelet ≥ 100x109/l and haemoglobin > 8 g/dl
•Total bilirubin ≤ 1.5N, AST ≤ 2.5N, ALT≤ 2.5N or AST/ALT ≤ 5N in case of liver metastass.
•Age ≥ 18 years
•ECOG Performance Status ≤ 1
•Signed and dated informed consent, and willing and able to comply with protocol requirements.
•Women of childbearing potential, as well as men (who have sexual relations with women of childbearing potential) must agree to use an effective method of contraception throughout this study and during the 6 months following administration of the last dose of the study medicinal product
•Patient who is a beneficiary of the Social security system |
•Carcinome neuroendocrine peu différencié de grade 3 ou MINEN avec composante de carcinome neuroendocrine peu différencié de grade 3 représentant ≥ 30% de la tumeur
•Tumeur primitive d’origine gastro-entéro-pancréatique ou inconnue
•À petites cellules ou à grande cellules ou non à petites cellules ou non typable
•Maladie métastatique
•1ère ligne de traitement pour une maladie métastatique. Pas de chimiothérapie ou de traitement systémique à visée antitumorale préalable
•Au moins une lésion mesurable selon les critères RECIST 1.1 évaluée par scanner ou IRM
•Bloc tumoral disponible
•PNN≥ 1.5x109/l, plaquettes≥ 100x109/l and hémoglobine > 8 g/dl
•Bilirubine totale ≤ 1.5N, ASAT ≤ 2.5N, ALAT≤ 2.5N or ASAT/ALAT ≤ 5N en cas de métastases hépatiques
•Age ≥ 18 ans
•Status de performance ECOG ≤ 1
•Patient en capacité de comprendre les modalités de l’essai thérapeutique, de signer le consentement éclairé et de se conformer aux exigences du protocole
•Les femmes en âge de procréer ainsi que les hommes (ayant des rapports sexuels avec des femmes en âge de procréer) doivent s’engager à utiliser des moyens de contraception efficaces tout au long de l’étude et au cours des 6 mois suivant l’administration de la dernière dose du médicament à l’étude
•Patient affilié à la sécurité sociale |
|
| E.4 | Principal exclusion criteria |
•Grade 3 well differentiated neuroendocrine tumor according to WHO 2017 classification
•Severe renal impairment (creatinine clearance less than 30 mL/min, MDRD)
•Partial or complete Dihydropyrimidine Dehydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL)
•Gilbert’s syndrome
•Pre-existing permanent neuropathy (NCI CTC V4.0 grade ≥2)
•Previously treated by chemotherapy or targeted therapy
•Brain metastases unless they are asymptomatic or under stable corticosteroid doses for 2 weeks otherwise. Radiation therapy prior to inclusion is required if symptomatic.
•Combination with sorivudine and others analogues as brivudine (irreversibly inhibits the enzyme dihydropyrimidine dehydrogenase)
•Treatment with St John’s Wort (Hypericum perforatum)
•Pregnant women or breastfeeding mother
•Known or historical active infection with HIV, or known active infection untreated with hepatitis B or hepatitis C
•History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years.
•Active or suspected acute or chronic uncontrolled disease that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
•vaccinations (live vaccine) within 30 days prior to start of study drugs
•Patient under guardianship and/or deprived of his/her freedom
•QT/QTc interval > 450 msec for male and > 470 msec for female at EKC.
•K+ < LLN, Mg²+ < LLN, Ca²+ < LLN
•History or know hypersensitivity to any of the study chemotherapy agents, or their excipients |
•Tumeur neuroendocrine de grade 3 bien différenciée selon la classification OMS 2017
•Insuffisance hépatiques sévère (clairance de la creatinine inférieure à 30mL/min, MDRD)
•Deficit partiel ou complete en Dihydropyrimidine Dehydrogenase (DPD) (uracilémie ≥ 16 ng/mL)
•Maladie de Gilbert
•Neuropathie préexistante permanent (NCI CTC V4.0 grade ≥2)
•Précédemment traité par chimiothérapie ou thérapie ciblée
•Métastases cérébrales sauf si elles sont asymptomatiques ou stables sous corticothérapie pendant deux semaines. La radiothérapie est nécessaire avant inclusion s’il y a des symptômes
•Association avec la sorivudine et autres analogues inhibiteurs de la DPD comme la brivudine
•Traitement par millepertuis (Hypericum perforatum)
•Femme enceinte ou allaitante
•patient séropositif pour VIH, hépatite B ou C ou autres syndromes d’immunodéficience
•antecedent de pathologie maligne dans les trois dernières années à l’exception du carcinome basocellulaire de la peau ou du carcinome in situ du col utérin correctement traités
•Maladie chronique non contrôlée ou infection active incompatible avec une participation à l’étude
•vaccination (vaccin vivant) dans les 30 jours précédant le début du traitement
•Personne privée de liberté ou sous tutelle
•Intervalle QT/QTc > 450 msec pour les hommes et > 470 msec pour les femmes à l’ECG
•K+ < LIN, Mg²+ < LIN, Ca²+ < LIN
•Antécédents ou hypersensibilité connue à l’un des agents de chimiothérapie de l’étude ou à leurs excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To compare the progression-free survival (PFS) with mFOLFIRINOX regimen versus platinum - etoposide regimen according to the investigator using RECIST v1.1 criteria. |
| Comparer la survie sans progression (SSP) entre le bras de traitement mFOLFIRINOX et le bras de traitement platinum – etoposide selon l’investigateur et évaluée selon les critères RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•PFS according to the centralized review (RECIST v1.1 criteria)
•Best objective response rate (ORR)
•Median overall survival (OS)
•Safety according to NCI CTC V4.0
•Dose-reductions
•Quality of life assessed by EORTC QLQ-C30 and EQ-5D-5L
•To establish a molecular profile within 2 months after tumor sample submission for each patient enrolled in the study and to provide a molecular tumor board report to the treating physician.
•Frequency of Rb loss in G3 NEC irrespective of the SC or LC subtype
•Correlation of ORR, PFS and OS under both chemotherapy regimens with molecular alterations (Rb, TP53, MSH2…) |
•SSP selon la relecture centralisée (critères RECIST v1.1)
•Taux de meilleure réponse objective (TRO)
•Survie globale (SG)
•Evènements indésirables selon le NCI CTC V4.0
•Dose intensité - réductions de dose
•Qualité de vie évaluée par les questionnaires EORTC QLQ-C30 et EQ-5D-5L
•Etablir un profil moléculaire dans les 2 mois après l’envoi de l’échantillon de la tumeur pour chaque patient inclus dans l’étude et fournir un compte-rendu de RCP moléculaire à l’investigateur traitant le patient.
•Nombre de pertes d’expression de Rb (indépendamment du sous-groupe petites cellules ou grandes cellules)
•Corrélation de TRO, SSP et OS sous les deux bras de traitement avec les altérations moléculaires (Rb, TP53, MSH2…)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| etoposide + sels de platine |
| etoposide and platinium |
|
| 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 | 60 |
| 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 | Yes |
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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