Gemcitabine-Cisplatin Plus Envafolimab in Resectable Biliary Tract Malignancies

The Efficacy and Safety of Gemcitabine-Cisplatin Plus Envafolimab as Neoadjuvant Therapy in Resectable Biliary Tract Malignancies at High Risk of Recurrence

This trial is to evaluate the efficacy of Gemcitabine-Cisplatin (GC) plus Envafolimab neoadjuvant therapy in the patients at high risk of recurrence. Primary endpoint: Major Pathologic Response (MPR). It will also learn about the safety of drug including Gemcitabine-Cisplatin (GC) plus Envafolimab as a neoadjuvant therapy in this trial.

This trial is a single-arm interventional clinical study to evaluate the efficacy and safety of neoadjuvant gemcitabine-cisplatin plus Envafolimab in resectable biliary tract malignancies patients with high-risk of recurrence. Patients with high-risk factors for recurrence. The criteria were defined as meeting at least one of the following: a. Preoperative CA19-9 ≥ 200 U/mL; b. Tumor diameter ≥5 cm or multiple tumor nodules on imaging; c. Regional lymph node metastasis with a short-axis diameter ≥ 1.0 cm on imaging; d. Vascular invasion (portal vein or hepatic artery) on imaging; e. Low or undifferentiated histologic grade. The primary endpoint: Major Pathologic Response (MPR). Secondary endpoints: Overall Survival (OS), Disease-free survival (DFS), Objective Response Rate (ORR) per the Response Evaluation Criteria In Solid Tumors (RECIST v1.1), Pathologic Response Rate (PCR), and R0 resection rate. The incidence and severity of adverse events (AEs), serious adverse events (SAEs), and laboratory test abnormalities judged as per the CTCAE v5.0 criteria. Exploratory endpoint: Relationship between carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), Pathological biomarker expression, spatial transcriptome (if samples are sufficient), gut microbiome metagenome sequencing, and treatment response.

Inclusion Criteria:

• Participants who have signed a written Informed Consent Form (ICF);
• Male or female participants aged 18-80 years;
• Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0/1;
• Biliary Tract Cancer (BTC) diagnosed by puncture pathology prior to enrollment;
• Participants must meet the following requirements for major vital organ function: a. Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L; platelet count ≥ 90×10⁹/L; hemoglobin ≥ 9 g/dL; b. Coagulation function: international normalized ratio (INR) ≤ 1.2; c. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3 times the upper limit of normal (ULN); d. Serum albumin ≥ 3.5 g/dL; total bilirubin ≤ 1.5 times the ULN. Patients with obstructive jaundice who meet the eligibility criteria after percutaneous transhepatic cholangial drainage or endoscopic retrograde cholangiopancreatography treatment are also eligible for enrollment; e. Child-Pugh class A or B; f. Serum creatinine ≤ 1.5 times the ULN;
• Patients with high-risk factors for recurrence. The criteria are defined as meeting at least one of the following: a. Preoperative CA19-9 ≥ 200 U/mL; b. Tumor diameter ≥ 5 cm or multiple tumor nodules on imaging; c. Regional lymph node metastasis with a short-axis diameter ≥ 1.0 cm on imaging; d. Vascular invasion (portal vein or hepatic artery) on imaging; e. Low or undifferentiated histologic grade;
• Participants who have at least 1 measurable lesion (RECIST v1.1);
• Be able to provide fresh stool samples and liver samples if undergoing surgery.

Exclusion Criteria

• Pathological diagnosis of hepatocellular carcinoma, mixed hepatocellular carcinoma, and other non-cholangiocarcinoma malignant tumor components;
• Prior systemic therapy for BTC, including immunotherapy, targeted therapy, or chemotherapy;
• History of other prior or concurrent malignancies, except those with complete treatment and disease-free survival for more than 5 years;
• Presence of an active, known or suspected autoimmune disease, or requirement for long-term systemic corticosteroid therapy (equivalent to ≥ 10 mg prednisone daily) or other immunosuppressive agents. Participants using inhaled or topical corticosteroids will not be excluded;
• Presence of ascites, hepatic encephalopathy, sclerosing cholangitis, or other concurrent organ dysfunctions that would preclude tolerance of general anesthesia or hepatectomy;
• Women who are breastfeeding or pregnant;
• Any other factors that, in the investigator's judgment, may compromise participant safety or trial compliance, including serious comorbidities requiring ongoing treatment, clinically significant laboratory abnormalities, or relevant social or family-related issues.