Sintilimab Combined with IBI310 and Surufatinib for the Treatment of G3-NET and NEC (NESSIE)

Inclusion Criteria:

• Patients who included in this study must fulfil all of the following criteria:

1. Fully aware of this study and voluntary to sign the informed consent form (theinformed consent form must be signed before any trial-specific procedure isperformed);

2. Aged 18-75 (inclusive);

3. Histologically or cytologically confirmed patients with inoperable ormetastatic high-grade neuroendocrine neoplasm (Ki67 index > 20% or with mitoticcount of more than 20 mitoses per high power field);

4. Patients who failed to receive standard treatment (Have progressed on previoustreatment, or treatment toxicity and side effects are not tolerated), or cannotreceive standard treatment (including patients who are intolerant to standardtreatment, who are judged by the investigator to be unsuitable for standardtreatment or who refuse to receive standard treatment), or who have no standardtreatment plan;

5. Having clear measurable lesions (according to RECIST 1.1). If the lesion is theonly one that has received previous local treatment (radiotherapy, ablation,vascular intervention, etc.), there must be clear imaging evidence of diseaseprogression in that lesion;

6. Agree to provide tumor specimens (for further diagnosis of pathological grade,detection of PD-L1 expression and lymphocyte infiltration);

7. ECOG performance status of 0 or 1;

8. Brain metastases are asymptomatic or stable after local treatment are allowedto be enrolled as long as they meet the following conditions:

1. Measurable lesions are outside of the central nervous system 2) No centralnervous system symptoms or no exacerbation of symptoms for at least 2 weeks 3)No glucocorticoid treatment or discontinuation of glucocorticoid treatmentwithin 7 days before first dose of study treatment.

9. Patients were allowed to receive palliative radiation therapy, but it ended 14days before the first dose of study treatment, and the radiation-relatedtoxicity returned to grade 1 or less (CTCAE5.0); 10. Predicted survival ≥ 3months; 11. Patients with adequate organ functions whose laboratory testswithin 7 days before the first dose meet the following requirements:

10. Absolute neutrophil count (ANC) ≥1.5x109/L within 14 days, without use ofgranulocyte colony-stimulating factor or other hematopoietic stimulatingfactor.

11. Platelet count ≥100×109/L within 14 days, without blood transfusion or use ofblood product.

12. Hemoglobin ≥ 9 g/dL within 14 days, without blood transfusion orerythropoietin.

13. Total bilirubin ≤1.5 × upper limit of normal (ULN); Such as total bilirubin > 1.5×ULN, but direct bilirubin ≤ ULN was also allowed.

14. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALTor AST ≤5×ULN in patients with liver metastasis).

15. Serum creatinine ≤1.5×ULN and creatinine clearance rate ≥60 mL /min (calculatedaccording to the Cockcroft-Gault formula).

16. Good coagulation function, defined as International normalized ratio (INR) orprothrombin time (PT) ≤1.5 ULN;

17. Normal thyroid function, defined as thyroid stimulating hormone (TSH) withinthe normal range. If the baseline TSH is outside the normal range, subjectswith total T3 (or FT3) and FT4 within the normal range can be enrolled;Hypothyroidism that can be controlled only by thyroid hormone replacementtherapy can be enrolled;

18. The myocardial enzyme profile is within the normal range (if the investigatorcomprehensively determines that the simple laboratory abnormality is notclinically significant, the patients is allowed to be enrolled); 12. Females ofchildbearing potential must have a negative urine or serum pregnancy testwithin 3 days prior to the first dose (Day 1 of Cycle 1). If a urine pregnancytest result cannot be confirmed as negative, a blood pregnancy test isrequested. All female patients will be considered to be of childbearingpotential unless they are naturally postmenopausal, underwent artificialmenopause, or are surgically sterile (e.g., hysterectomy, bilateraladnexectomy).

19. If there is a risk of conception, Male or female patients of childbearingpotential volunteer to use effective contraceptive methods (failure rate ≤ 1%)during the study and within 120 days after last administration of the studydrug.

Exclusion Criteria:

• Subjects must be excluded from this study when any one of the following criteria ismet:

1. Presence of other malignancies in the past 5 years (except for basal cellcarcinoma or squamous cell carcinoma of the skin and carcinoma in situ of thecervix, which were effectively controlled);

2. Currently participate in an interventional clinical study, or have been treatedwith another study drug or medical equipment within 4 weeks prior to the firstdose;

3. Previous use of anti (PD-1), anti-PD-L1, anti-PD-L2 or CTLA-4 antibody or anyother antibody acting on T cell co-stimulatory or checkpoint pathways (including but not limited to OX-40, CD137, etc.), anti-VEGF/VEGFR-targeteddrugs;

4. Having abnormal thyroid function with symptoms ongoing or requiring treatmentat screening (only hypothyroidism that can be controlled by thyroid hormonereplacement therapy can be included);

5. Received systemic therapy with anti-neuroendocrine tumor of proprietary Chinesemedicines or immunomodulatory drugs (including thymosin, interferon andinterleukin, except for local control of pleural effusion) within 2 weeks priorto the first dose;

6. Patients with any active autoimmune disorders requiring systematic treatment (e.g., palliative drugs, glucocorticoids, or immunosuppressants) or a historyof autoimmune disease in the past 2 years. Alternative therapies (e.g.thyroxine, insulin, or physiologic glucocorticoids for adrenal or pituitarydysfunction) are not considered systemic;

7. Use of immunosuppressant within 7 days prior to the first dose, not includinglocal glucocorticoid via nasal spray, inhalation or other routes or systemicglucocorticoid at physiological dose. Note: Physiological doses ofglucocorticoids (≤10 mg/ day of prednisone or equivalent dose) are permitted;

8. Uncontrollable malignant hydrothorax, ascites or pericardial effusion (patientswho do not need drainage effusion or who stop drainage for 3 days withoutsignificant increase in effusion can be included in the group);

9. Use of CYP3A potent or moderate inducers during the administration ofconcomitant medications or within 1 weeks or 5 half-lives (whichever is longer)prior to the first dose (Appendix 3);

10. Patients who currently have gastric and duodenal active ulcer, ulcerativecolitis, or active bleeding in the unresected tumor, or seriousgastrointestinal disorders, or other conditions that may cause haemorrhage ofdigestive tract or perforation;

11. Patients with evidence or history of obvious bleeding tendency within 2 monthsprior to the first dose. (bleeding within 2 months > 30 mL, hematemesis, blackfeces), hemoptysis (within 4 weeks > 5 mL of fresh blood);

12. Allogeneic organ transplantation (except corneal transplantation) or allogeneichematopoietic stem cell transplantation;

13. A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to the study drugs (Sintilimab, IBI310, Surufatinib), or aprior history of severe allergy to any other monoclonal antibody.

14. Patients with multiple factors affecting oral medication (such as inability toswallow, post-gastrointestinal resection, chronic diarrhea and intestinalobstruction);

15. Toxicity from a previous anti-tumor treatment that does not return to Grade 0or 1 (except for hair loss);

16. Human immunodeficiency virus (HIV) antibody positive;

17. Untreated active hepatitis B (defined as HBsAg positive with HBV-DNA copynumber greater than the upper limit of the normal value in the laboratorydepartment of the research center);Note: Hepatitis B subjects who meet the following criteria can also beenrolled:

1. HBV viral load before initial administration < 1000 copies/mL (200 IU/ml).Subjects should receive anti-HBV therapy to avoid virus reactivation 2) Forpatients with HBc (+), HBsAg (-), anti-HBS (-), and HBV viral load (-),prophylactic anti-HBV therapy is not required, but rigorous monitoring of virusreactivation is required;

18. Patients with known positive hepatitis C virus antibody (HCV Ab) and HCV RNA > 1 × 103 copies/mL;

19. Vaccination of any live or attenuated live vaccine within 4 weeks prior to thefirst dose or during the study; Note: Acceptance of injectable inactivatedvirus vaccine against seasonal influenza is permitted within 30 days prior tofirst dose; Intranasally administered live attenuated flu vaccines are notallowed;

20. Pregnant (positive pregnancy test prior to administration) or lactating women;

21. Presence of any serious or uncontrollable systemic illness;

22. Other disease, metabolic disorder, physical examination anomaly, abnormallaboratory result, or any other condition that investigators suspect mayprohibit use of the investigational product, affect interpretation of studyresults, or put the patient at high risk.