AK112 Combined With GAP Conversion Therapy for Locally Advanced Gallbladder Cancer (ICORE-GBC)

Inclusion Criteria:

1. Voluntarily provide written informed consent;
2. Age ≥18 years and ≤75 years at enrollment;
3. Histologically or cytologically confirmed gallbladder adenocarcinoma;
4. Radiological assessment meeting any of the following criteria: a. Hepatic invasion requiring extensive hepatectomy that the patient cannot tolerate; b. Biliary tract invasion extending beyond the bifurcation threshold requiring extensive hepatectomy that the patient cannot tolerate; c. Regional lymph node metastasis with fused bulky lymph nodes (maximum short-axis diameter >2 cm) compressing or invading critical blood vessels/biliary tracts, precluding radical lymphadenectomy; d. Primary tumor vascular invasion: main portal vein or left portal branch invasion without feasible vascular reconstruction; proper hepatic artery/common hepatic artery invasion >180°, or invasion <180% combined with mandatory portal vein reconstruction; right portal vein/right hepatic artery invasion with intolerance to extensive hepatectomy;e. Direct invasion of adjacent organs (pancreas, stomach, duodenum, colon);
5. MDT consensus confirming initial non-resectability, with anticipated feasibility of radical resection after conversion therapy;
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
7. No prior systemic anti-tumor therapy for locally advanced gallbladder cancer;
8. At least one measurable target lesion per RECIST v1.1 suitable for repeated accurate quantitative measurement;
9. Adequate organ function to tolerate the conversion regimen;
10. Estimated survival ≥3 months;
11. Willing and able to comply with scheduled visits, treatment regimens, laboratory testing, and all other study requirements;

12. Adequate hematologic, renal, hepatic, coagulation, and cardiac function confirmed by screening laboratory tests (no blood product/growth factor support within 7 days prior to screening lab draws):

    a. Hematology: i. Absolute Neutrophil Count (ANC) ≥1.5 × 10⁹/L (1,500/mm³) ii. Platelet count ≥100 × 10⁹/L (100,000/mm³) iii. Hemoglobin ≥90 g/L; b. Renal function: i. Calculated Creatinine Clearance (CrCl) ≥50 mL/min via the Cockcroft-Gault formula: CrCl (mL/min) = [(140 - Age) × Weight (kg) × F] / [Serum Creatinine (mg/dL) × 72] F = 1 for males, F = 0.85 for females; SCr = serum creatinine. ii. Urine protein ≤1+ or 24-hour urine protein quantification <1.0 g; c. Hepatic function: i. Total bilirubin (TBil) ≤ 2 × the upper limit of normal (ULN); ii. AST and ALT ≤2.5 × ULN; iii. Serum Albumin (ALB) ≥28 g/L; d. Coagulation function: International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤1.5 × ULN; e. Cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥50% on echocardiogram.

Exclusion Criteria:

1. Histological or cytological confirmation of gallbladder non-adenocarcinoma: squamous cell carcinoma, neuroendocrine neoplasm, lymphoma, sarcoma;
2. Presence of distant metastatic disease at screening;
3. Prior radiotherapy, chemotherapy, targeted therapy, or immunotherapy for gallbladder cancer;
4. Concurrent other malignant tumors besides gallbladder cancer;
5. Severe uncontrolled biliary tract infection or untreated obstructive jaundice;

6. Major surgery or severe trauma within 30 days prior to first study drug administration:

   1. Definitions:

      Major surgery: All open/laparoscopic procedures requiring general endotracheal anesthesia entering thoracic, abdominal, or pelvic cavities (e.g.,, exploratory laparotomy, gastrointestinal resection, hernia repair, partial hepatectomy); Severe trauma: Deep tissue injury, visceral rupture requiring hospitalization or surgical repair (e.g., fractures, extensive soft-tissue contusion, closed abdominal trauma);

   2. Minimally invasive/interventional procedures permitted with mandatory washout intervals:

   Diagnostic biopsy (lymph node, liver/gallbladder fine needle, EUS biopsy): minimum 7 days between the procedure and the first drug administration, no active hemorrhage/hematoma; Biliary decompression (PTCD, ERCP stent/nasobiliary drainage): a minimum of 14 days between the procedure and the first drug administration, no active hemorrhage, peritonitis, or biliary leakage confirmed by clinical and radiological evaluation;

7. Active autoimmune disease, active inflammatory bowel disease, congenital or acquired immunodeficiency, active pulmonary tuberculosis, active syphilis infection, prior solid organ or allogeneic hematopoietic stem cell transplantation, or non-infectious interstitial lung disease requiring long-term systemic corticosteroid therapy;

8. Severe bleeding diathesis or coagulation disorder history:

   1. Screening lab abnormalities: PLT <100 ×10⁹/L; INR >1.5 (without anticoagulation); APTT >1.5 × ULN; Fibrinogen <1.5 g/L;
   2. CTCAE Grade ≥2 active bleeding event within 3 months before enrollment, or uncontrolled major vascular complications;
9. Confirmed hypersensitivity to any excipient or active component of the study drugs;
10. Pregnant or lactating female patients;
11. Severe psychiatric disorder, history of substance dependence, or other medical conditions that may impair trial compliance throughout study participation.