Two Chemotherapy Regimens Plus or Minus Bevacizumab

• Well differentiated pancreatic neuroendocrine tumor grade 1 (NET G1), grade 2 (NET G2) or grade 3 (NET G3)*

*Grade 3 tumor must be confirmed by a pathologist of the TENpath network.

• Indication for chemotherapy for locally advanced or metastatic disease with proven progression (at least 20% increase of tumor size on a maximum of 12 months period of follow-up) or other indication of chemotherapy following the National Thesaurus of GI Cancerology (Appendix 6) (liver involvement > 50%, symptoms related to the tumour or its metastases, Ki67>10%)
• Patient with at least one measurable target tumor by RECIST 1.1 and that has never been irradiated
• Patient with a life expectancy greater than 3 months
• Men or women with performance status (ECOG) ≤ 2 (Appendix 3)
• Age ≥ 18 years
• Adequate hematological function: neutrophil count (ANC) ≥ 1.5x109/L, platelets greater than 75x109/L, hemoglobin greater than 10g/dl (blood transfusions are accepted to reach this level).
• Adequate liver function: serum bilirubin lower than 3 x upper limit of normal (ULN); aminotransferases and alkaline phosphatase levels lower than 2.5 ULN (lower than 5 ULN if liver metastases), TP greater than 50 %
• Proteinuria lower than 1g/24h, blood creatinine less than 120 μmol/L and creatinin clearance ≥ 60 ml/min as calculated by Cockroft-Gault formula Note: a negative dipstick urine analysis is sufficient.
• Absence of active bleeding, coagulopathy or pathologic condition that would confer a high risk of bleeding
• Prior treatment with somatostatin analogues, everolimus or sunitinib is allowed
• Negative serum pregnancy test ≤ 72 hours before randomization (for women of childbearing potential only). Sexually active women of childbearing potential must agree to use a highly effective method of contraception or to abstain from sexual activity during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception.
• Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
• Patient affiliated to a social security regimen or beneficiary of such regimen

Non inclusion criteria :

• Disease accessible to resection or percutaneous method of destruction
• Any known allergy or contraindication to the treatments used in the trial
• Patients with a complete DPD deficiency; defined as an uracil concentration ≥150ng/ml Note: patients with a suspicion of partial DPD deficiency, defined as a uracil concentration ≥ 16 ng/ml and < 150 ng/ml, will receive an adapted 1st cycle dose, according to a clinic-biological discussion. The dose can be then readapted for the second cycle according to the tolerability of the treatment during the 1st cycle.
• Patient previously treated with chemotherapy for the neuroendocrine tumour
• Patient have received any other antitumor therapy: chemotherapy, immunotherapy
• Other serious diseases such as respiratory failure or congestive heart failure, angina pectoris not medically controlled; history of myocardial infarction within 6 months prior to study entry, uncontrolled hypertension and arrhythmias, concomitant severe infection or uncontrolled diabetes mellitus
• Subjects with a history of chronic or acute hepatitis C or B infection.
• Surgery during the 5 weeks preceding the randomization
• History of cancer (except basal cell skin or carcinoma in situ carcinoma of the cervix) within 5 years prior to entry into the trial. But patients with cancers that have been treated more than 5 years ago and are considered as cured are eligible.
• Neurological or psychiatric pathology that may interfere with adherence to treatment
• Patients have received yellow fever vaccine within 30 days prior to the first dose of trial treatment.
• Patient with pernicious anaemia and other megaloblastic anaemias secondary to the lack of Vitamin B12
• Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
• Hypersensitivity to study drugs or any of its excipients
• Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent
• Pregnant or breast feeding women