A Multicenter, Prospective, Randomized, Open-label Phase Ib/II Study of Celecoxib Plus Pembrolizumab and Gemcitabine/Cisplatin Versus Pembrolizumab and Gemcitabine/Cisplatin in Patients With CK5/6-High Unresectable Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma

Inclusion criteria

• Age ≥ 18 years.
• Histologically or cytologically confirmed intrahepatic cholangiocarcinoma (iCCA).
• Unresectable locally advanced, recurrent, or metastatic disease.
• No prior systemic therapy for advanced disease.
• At least one measurable lesion according to RECIST v1.1.
• ECOG performance status of 0-1.
• Availability of adequate pre-treatment tumor tissue for central pathological review.
• CK5/6 H-score ≥ 1.0 as determined by central laboratory testing.
• Adequate organ and bone marrow function as defined by protocol-specified laboratory criteria.
• Patients with biliary obstruction must have undergone effective drainage and achieved clinical stabilization prior to enrollment.
• Ability to provide written informed consent.

Exclusion criteria

• Other primary malignancies including extrahepatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma.
• CK5/6 H-score < 1.0.
• Prior systemic therapy for advanced or metastatic disease.
• Active gastrointestinal bleeding, peptic ulcer disease, or high risk of gastrointestinal perforation.
• Recent history of significant cardiovascular events including myocardial infarction, stroke, uncontrolled hypertension, or severe heart failure.
• Known hypersensitivity to celecoxib, sulfonamides, NSAIDs, or aspirin-exacerbated respiratory disease.
• Active autoimmune disease or conditions contraindicating pembrolizumab therapy.
• Severe renal impairment.
• Child-Pugh class C hepatic impairment.
• Active uncontrolled infection.
• Any condition that, in the investigator's opinion, would interfere with study participation or interpretation of results.