AK112 Combined With GAP Conversion Therapy for Locally Advanced Gallbladder Cancer

Single-Center, Single-Arm, Two-Stage, Prospective Phase II Clinical Study of AK112 Combined With GAP Regimen as Conversion Therapy for Locally Advanced Gallbladder Cancer

The goal of this clinical trial is to evaluate the efficacy and safety of AK112 combined with the GAP regimen as conversion therapy for patients with locally advanced gallbladder cancer who are initially considered unsuitable for curative surgery.

The main questions this study aims to answer are:

1. Whether AK112 combined with the GAP regimen can increase the rate of successful R0 radical resection after conversion therapy.
2. Whether this treatment approach can achieve tumor response and disease control with acceptable safety in patients with locally advanced gallbladder cancer.

Participants will receive AK112 combined with gemcitabine, cisplatin, and albumin-bound paclitaxel (GAP regimen) every 21 days for 4-6 treatment cycles. Tumor response will be evaluated by CT or MRI according to RECIST version 1.1 criteria. Patients who become eligible for surgery after multidisciplinary evaluation will undergo radical resection. All participants will be monitored for treatment-related adverse events, disease progression, and survival outcomes during follow-up.

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.