A Trial of Cabozantinib in Patients With Advanced, Low Proliferative NEN G3

Inclusion Criteria:

1. Patient with histologically confirmed diagnosis of neuroendocrine neoplasia;

2. Tumor proliferation rate has to be between Ki67 20% to 60% (local assessment);

3. Male, female, or diverse patients aged > 18 years without upper age limit;

4. At least one measurable tumor lesions in CT or MRI scan;

5. Newly diagnosed or progressive disease assessed per RECIST criteria 1.1;

6. Patients must have a performance status of ECOG 0-2;

7. Patients must have a life expectancy of more than 3 months;

8. Hb> 9 mg/dl;

9. platelets >80T/µl;

10. white blood cells >3T/μL;

11. total bilirubin <3mg/dl;

12. AST and ALT <4xN;

13. Serum creatinine <2mg/dl, eGFR >40mL/min/1.73m2;

14. BUN <5xN;

15. lipase <3xN;

16. albumin ≥2.8 g/dL;

17. PT/PTT ≤ 1.5 × ULN;

18. urine protein: creatinine ratio ≤ 1;

19. Written informed consent obtained according to international guidelines and locallaws;

20. Ability to understand the nature of the trial and the trial related procedures andto comply with them;

Exclusion Criteria:

1. Patients younger than 18 years;

2. Patients with Mixed Neuroendocrine-Non-neuroendocrine Neoplasia (MINEN);

3. Patients with former treatment with TKI or VEGF receptor antagonist;

4. Patients with additional malignancy <5 years in medical history (exclusion:non-invasive skin cancer);

5. Patients with symptomatic brain metastases;

6. Patients with Known HIV infection, infectious hepatitis (type A, B or C) or anotheruncontrolled infection;

7. Patients with Known hypersensitivity to Cabozantinib or contraindications fortreatment with Cabozantinib according to Summary of Product Characteristics (SmPC);

8. Patients with class III or IV congestive heart failure;

9. Patients with QTc more than 500 ms or 140% of normal range according to age;

10. Patients with uncontrolled hypertension;

11. Patients with severely impaired lung function;

12. Patients with history of organ transplant (exclusion: cornea transplantation);

13. Patients with clinical apparent acute or chronic gastric ulceration;

14. Patients with history of hemophilia;

15. Patients with surgery at the GI tract within the last 12 weeks;

16. Patients with patients with uncontrolled inflammatory bowel disease;

17. Simultaneous participation in other interventional trials which could interfere withthis trial; simultaneous participation in registry and diagnostic trials is allowed

18. Patient without legal capacity who is unable to understand the nature, significanceand consequences of the trial;

19. Previous participation in this trial

20. concomitant use of therapeutic anticoagulation or strong CYP3A4 inducers orinhibitors (e.g. amiodarone);

21. Known or persistent abuse of medication, drugs or alcohol;

22. Person who is in a relationship of dependence/employment with the sponsor or theinvestigator;

23. Patients who cannot give informed consent;

24. Current or planned pregnancy, nursing period;