Efficacy and Safety of Chidamide+Sintilimab+Bev as Second-Line Therapy in Advanced Extrapulmonary Neuroendocrine Carcinoma

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.