FIRST LINE CHEMOTHERAPY FOR METASTATIC GASTRO ENTERO PANCREATIC NEUROENDOCRINE CARCINOMA

Prior treatment

• Treatment with St John's Wort (Hypericum perforatum)
• vaccinations (live vaccine) within 30 days prior to start of study drugs
• Patient already participating in another clinical trial who is currently being treated or whose treatment was completed less than four weeks prior to inclusion.
• Previously treated by chemotherapy or targeted therapy
• Symptomatic brain metastases patient with asymptomatic brain metastases or under stable corticosteroid doses for at least 2 weeks before randomization can be included.

Other illness

• Known or historical active infection with HIV, or known active infection untreated with hepatitis B or hepatitis C
• History of prior malignancy in the three yars before randomization, except for cured non-melanoma skin cancer and cured in situ cervical carcinoma.
• 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
• History or know hypersensitivity to any of the study chemotherapy agents, or their excipients.
• Known Gilbert's syndrome

Lab values

• QTc interval > 450 msec for male and > 470 msec for female at EKC.
• Severe renal impairment (creatinine clearance less than 30 mL/min, Cockroft and Gault)

Other

• Grade 3 well differentiated neuroendocrine tumor according to WHO 2017 classification
• Pregnant women or breastfeeding mother
• Patient under guardianship and/or deprived of his/her freedom
• K+ < LLN, Mg²+ < LLN, Ca²+ < LLN
• ECOG performance status > 1
• Partial or complete Dihydropyrimidine Dehydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL)
• Pre-existing permanent neuropathy (NCI CTC V4.0 grade ≥2)
• Combination with sorivudine and others analogues of dihydropyrimidine dehydrogenase)

• Grade 3 neuroendocrine carcinoma (Ki67>20%) or high grade MiNEN with a grade 3 poorly differentiated neuroendocrine carcinoma
• Total bilirubin ≤ 1.5N, AST ≤ 2.5N, ALT≤ 2.5N or AST and ALT ≤ 5N in case of liver metastasis.
• Age ≥ 18 years
• 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
• Primary gastro-entero-pancreatic or unknown primary
• Small cell or large cell or non-small cell or non- typeable neuroendocrine carcinoma
• Metastatic disease
• ECOG performance status ≤ 1
• First line treatment for metastatic disease. No prior chemotherapy or systemic therapy for management of metastatic disease or primary tumor
• 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