This is a single-arm, multicenter phase Ⅱ study to evaluate the therapeutic efficacy and safety of chidamide + sintilimab + bevacizumab in subjects with advanced extrapulmonary neuroendocrine carcinoma who have failed first-line standard therapy. The primary purpose is to assess the objective response rate (ORR) of chidamide + sintilimab + bevacizumab in the above-mentioned subjects, with a planned enrollment of 34 subjects with advanced extrapulmonary neuroendocrine carcinoma who have failed first-line standard therapy.

This is a single-arm, multicenter phase Ⅱ clinical study. All eligible subjects will receive the unified treatment of chidamide + sintilimab + bevacizumab, with no control group set in the study. The treatment regimen for all enrolled subjects is 200 mg of sintilimab administered via intravenous drip once every 3 weeks (Q3W), 20 mg of chidamide administered orally twice a week (BIW) 30 minutes after meals, and 7.5 mg/kg of bevacizumab administered via intravenous drip once every 3 weeks (Q3W). The administration sequence of the intravenous drugs is as follows: sintilimab is given first with an infusion time of 60±15 minutes, and bevacizumab is administered at least 5 minutes after the completion of sintilimab infusion. The treatment will continue until disease progression, death, intolerable toxicity, withdrawal of informed consent, or other reasons specified in the study protocol, whichever occurs first, with the maximum treatment duration until disease progression. For subjects who are initially judged to have disease progression according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), if their clinical conditions are stable, the investigator will judge whether they can continue to receive the study drug treatment, and the disease progression will be confirmed according to the Immune Response Evaluation Criteria in Solid Tumors (iRECIST) 4~6 weeks later.

The primary endpoint of this study is the objective response rate (ORR) of chidamide + sintilimab + bevacizumab in the enrolled subjects, defined as the proportion of subjects achieving complete response (CR) or partial response (PR) evaluated by the investigator based on RECIST v1.1. The secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR) of the treatment, as well as the safety of chidamide + sintilimab + bevacizumab evaluated by the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and changes in vital signs, physical examination results, and laboratory test indicators.

A total of 34 subjects with advanced extrapulmonary neuroendocrine carcinoma who have failed first-line standard therapy will be enrolled in this study. The enrollment criteria require that subjects are pathologically or cytologically confirmed with unresectable locally advanced or metastatic extrapulmonary neuroendocrine carcinoma, have at least one measurable lesion according to RECIST v1.1, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0~1, an expected survival time of ≥12 weeks, and adequate organ and bone marrow function. Subjects with a history of exposure to anti-angiogenic targeted therapy or HDAC inhibitors, uncontrolled severe infections, symptomatic central nervous system metastasis, and other conditions that do not meet the inclusion criteria will be excluded from the study.

Efficacy assessments will be conducted using contrast-enhanced CT or MRI, with examinations covering the chest, abdomen, and pelvis. For subjects with suspected or known central nervous system metastasis, enhanced cranial MRI will be performed at the baseline. Tumor imaging evaluations will be conducted every 6 weeks (±7 days) within 24 weeks after the first dose of the study drug, and every 9 weeks (±7 days) after 24 weeks until the initiation of new anti-tumor therapy, disease progression, withdrawal of informed consent, or death. The primary efficacy analysis of ORR will estimate the proportion of subjects and calculate the 95% exact two-sided confidence interval (CI) using the Clopper Pearson method. For time-to-event indicators such as PFS, OS, and DOR, the Kaplan-Meier method will be used for analysis, and the median time, the rate at each time point, and their 95% CIs will be calculated.

Safety assessments will be conducted throughout the study period, including the screening period, treatment period, and follow-up period. All AEs, TEAEs, AESIs, and SAEs will be graded and recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0). Regular laboratory examinations include blood routine, coagulation function, blood biochemistry, myocardial markers, urine routine, fecal routine + occult blood, thyroid function, and viral serological tests. Vital signs, physical examinations, 12-lead electrocardiograms, and echocardiograms will be monitored at each study visit as scheduled. Serious adverse events will be reported by the investigator to the sponsor, drug regulatory authorities, and ethics committee within 24 hours of awareness.

After the termination of study treatment, subjects will undergo a safety follow-up 30 days (±7 days) after the last dose of the study drug, and survival follow-up will be conducted every 90 days (±7 days) after the safety follow-up, which can be completed by telephone follow-up. The survival follow-up will continue until the subject's death or the end of the study to collect information related to overall survival and subsequent anti-tumor therapy.

Inclusion Criteria:

1. Histologically or cytologically confirmed locally advanced, unresectable, or metastatic extrapulmonary neuroendocrine carcinoma (NEC).
2. Failure of first-line standard systemic therapy, with documented disease progression during or after treatment by imaging or clinical evidence (e.g., cytology of new ascites or pleural effusion). Patients who discontinued first-line therapy due to intolerable toxicity are eligible.
3. At least one measurable lesion per RECIST version 1.1.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Able to provide written informed consent and comply with study visits and procedures.
6. Age ≥ 18 years and ≤ 75 years.
7. Life expectancy ≥ 12 weeks.
8. Women of childbearing potential and men with female partners of childbearing potential must use effective contraception throughout the treatment period and for 6 months after the last dose of study treatment.
9. Adequate organ and bone marrow function within 7 days before enrollment, without support treatments (blood products, growth factors, albumin) within 14 days before testing: absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count (PLT) ≥ 100 × 10⁹/L; hemoglobin (HGB) ≥ 9.0 g/dL; serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); ALT/AST ≤ 3.0 × ULN (no liver metastasis) or ≤ 5.0 × ULN (with liver metastasis); serum albumin ≥ 25 g/L; serum creatinine (Cr) ≤ 1.5 × ULN; urine protein < 2+ or 24-hour urine protein < 1 g if urine protein ≥ 2+; INR ≤ 1.5 × ULN and APTT ≤ 1.5 × ULN.

Exclusion Criteria:

1. Prior exposure to any anti-angiogenic therapy or histone deacetylase (HDAC) inhibitor.
2. Received any investigational drug within 4 weeks before the first dose of study treatment.
3. Simultaneously participating in another interventional clinical study (observational or follow-up studies are allowed).
4. Received last dose of anti-tumor therapy (chemotherapy, targeted therapy, immunotherapy, embolization, etc.) within 3 weeks before first dose.
5. Received radiotherapy within 4 weeks before first dose.
6. Residual radiation-related toxicity (e.g., pneumonitis, hepatitis, enteritis) from prior radiotherapy > 4 weeks before first dose, including symptomatic cases or those requiring corticosteroids.
7. Received systemic immunosuppressive drugs within 4 weeks before first dose, except topical/inhaled corticosteroids or physiological systemic corticosteroids (≤ 10 mg/day prednisone equivalent).
8. Received or plans to receive live attenuated vaccines within 4 weeks before first dose or during the study.
9. Underwent major surgery within 4 weeks before first dose, or has unhealed wounds, ulcers, or fractures.
10. Resolved toxicity from prior anti-tumor therapy not recovered to NCI CTCAE version 5.0 grade ≤ 1 (except alopecia or non-clinically significant laboratory abnormalities).
11. Known symptomatic central nervous system (CNS) metastases or carcinomatous meningitis. Patients with treated and stable CNS metastases for ≥ 4 weeks and neurological symptoms recovered to grade ≤ 1 are allowed.
12. Active autoimmune disease requiring systemic therapy within 2 years before first dose; or primary immunodeficiency. Replacement therapy (e.g., thyroid hormone, insulin) is permitted.
13. Active tuberculosis, or anti-tuberculosis treatment within 1 year before first dose.
14. Interstitial lung disease requiring corticosteroid treatment.
15. Active hepatitis B (HBsAg positive and HBV DNA ≥ 200 IU/mL) or active hepatitis C (HCV antibody positive and HCV RNA positive).
16. Known HIV infection or syphilis.
17. Severe uncontrolled active infection, including hospitalization for infection within 4 weeks before first dose.
18. Significant malnutrition requiring intravenous nutrition, unless corrected for > 4 weeks before first dose.
19. Symptomatic congestive heart failure (NYHA class II-IV), or symptomatic/uncontrolled arrhythmia.
20. Uncontrolled arterial hypertension despite optimal treatment (systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg).
21. Any arterial thromboembolic event (myocardial infarction, pulmonary embolism, unstable angina) within 6 months before enrollment.
22. History of deep vein thrombosis or other severe thromboembolism within 3 months before enrollment (catheter-related or superficial vein thrombosis excluded).
23. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh B or C cirrhosis.
24. History of gastrointestinal perforation/fistula, peptic ulcer, bowel obstruction, extensive bowel resection, Crohn's disease, ulcerative colitis, intra-abdominal abscess, or chronic diarrhea within 6 months before enrollment; or intestinal stent placement.
25. Uncontrolled metabolic disorders or other severe medical conditions that may increase study risk or confound result interpretation.
26. Hereditary bleeding tendency or coagulation disorder.
27. Any life-threatening bleeding event within 3 months before enrollment (requiring transfusion, surgery, or continuous treatment).
28. High bleeding risk per investigator assessment: severe esophageal/gastric varices, intermittent bleeding (e.g., hematochezia, hemoptysis).
29. Cerebrovascular accident (including transient ischemic attack) within 6 months before enrollment.
30. Use of aspirin (> 325 mg/day) or other platelet inhibitors for 10 consecutive days within 10 days before first dose.
31. Use of oral or parenteral anticoagulants or thrombolytics for 10 consecutive days within 10 days before first dose (prophylactic anticoagulation allowed).
32. Symptomatic or drainable pleural effusion, ascites, or pericardial effusion (only small asymptomatic effusions by imaging are allowed).
33. History of other primary malignancy, except: Malignancy in complete remission for ≥ 2 years without treatment during study；adequately treated non-melanoma skin cancer or carcinoma in situ with no evidence of recurrence.
34. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
35. Known hypersensitivity to any monoclonal antibody component or study drug excipients.
36. Pregnant or breastfeeding female patients.
37. History of alcoholism or drug abuse.
38. Any other acute or chronic disease, psychiatric disorder, or laboratory abnormality that, in the investigator's opinion, increases study risk or interferes with result interpretation.