The main objective of this clinical trial represents the evaluation of efficacy of the tyrosine kinase inhibitor Cabozantinib in patients with NEN G3 with a proliferation rate of Ki67 20 - 60%.

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 local laws;
20. Ability to understand the nature of the trial and the trial related procedures and to 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 another uncontrolled infection;
7. Patients with Known hypersensitivity to Cabozantinib or contraindications for treatment 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 with this trial; simultaneous participation in registry and diagnostic trials is allowed
18. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial;
19. Previous participation in this trial
20. concomitant use of therapeutic anticoagulation or strong CYP3A4 inducers or inhibitors (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 the investigator;
23. Patients who cannot give informed consent;
24. Current or planned pregnancy, nursing period;