Inclusion Criteria:
1. Age ≥ 18 years
2. Histologically proven neuroendocrine neoplasia NEN G3 (WHO 2010/2019)
3. One block or 20 slides (cut at 4 microns) of archival tumor tissue to perform central pathological review and biomarker assessment and for translational research
4. No curative option available
5. Progression within 9 months before study initiation and after at least one chemotherapy (platinum based chemotherapy or STZ/TEM/DTIC based chemotherapy)
6. Presence of measurable disease as per RECIST1.1 criteria
7. Adequate organ and bone barrow functionn:
1. Hematologic: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused)
2. Hepatic: total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 × ULN for subjects with documented metastatic disease to the liver)
3. Renal: estimated creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
8. Pregnancy and contraception:
1. Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential.
2. Contraception: Women of child-bearing potential (WOCBP) and men who are able to father a child, willing to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of study participation and for at least 30 days for female and 90 days for male patients after last dose of avelumab and at least for 4 months after last dose of cabozantinib
9. ECOG Performance Status 0 - 1
10. Life expectancy of at least 12 weeks according to the assessment of the investigator
11. Written informed consent: Signed and dated informed consent of the subject must be available before start of any specific trial procedures
12. Ability of subject to understand nature, importance and individual consequences of clinical trial.
Exclusion Criteria:
1. Merkel Cell carcinoma (MCC) or small cell lung cancer (SCLC)
2. Typical or Atypical Carcinoid of the lung with a Ki67 \< 20%
3. Prior therapy with any TKI or immune therapy
4. Neuroendocrine neoplasias that are potentially curable by surgery
5. Major surgery within 4 weeks before first dose of study medication. Complete wound healing must be observed at least 10 days prior to enrollment.
6. Patients who are at increased risk for severe haemorrhage
7. TACE, TAE, SIRT or PRRT within 8 weeks before first dose of study medication
8. Patients pretreated with Interferon as last treatment line prior to study entry
9. Concurrent anticancer treatment after start of trial treatment (e.g., cyto¬reductive therapy, TKI therapy, mTOR inhibitor therapy, radiotherapy \[with the exception of palliative radiotherapy\], immune therapy, or cytokine therapy except for erythropoietin or use of any investigational drug).
10. Concurrent treatment with strong inducers of cytochrome P450 3A4 (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort) and strong inhibitors of cytochrome P450 3A4 (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir), warfarin (due to its high protein bound)
11. Immunosuppressants: Current use of immunosuppressive medication, EXCEPT for the following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
12. Prior organ transplantation, including allogeneic stem cell transplantation
13. Active infection requiring systemic therapy
14. HIV/AIDS: Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
15. Hepatitis: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
16. Active SARS-CoV-2 infection (detected via positive PCR test)
17. Autoimmune disease: Severe active autoimmune disease that requires immunomodulatory therapy. Patients with diabetes type I, vitiligo, psoriasis, autoimmune thyroid disease not requiring immunosuppressive treatment are eligible.
18. Persisting toxicity related to prior therapy (NCI CTCAE v.5.0 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable
19. Pregnancy or lactation
20. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
21. Vaccination: Vaccination within 4 weeks before the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines.
22. Hypersensitivity to study drugs: Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3) and lactose contained in cabozantinib tablets
23. Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), uncontrolled arterial hypertension or serious cardiac arrhythmia requiring medication.
24. Clinical significant hematemesis or hemoptysis
25. Medical or psychological conditions that would jeopardise an adequate and orderly completion of the trial
26. Patients, who are legally institutionalized.
