Chemotherapy For Metastatic Grade 3 Poorly Differentiated NEuroendocrine Carcinoma Of GastroEnteroPancreatic And Unknown Primary

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 hemoglobin \> 8 g/dl
• Total bilirubin ≤ 1.5N, AST ≤ 2.5N, ALT≤ 2.5N or AST/ALT ≤ 5N in case of liver metastases.
• 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 15 months following administration of the last dose of the study medicinal product
• Patient who is a beneficiary of the Social security system

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