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

• Celecoxib + Pembrolizumab + Gemcitabine/Cisplatin (Drug): Celecoxib is administered orally at 200 mg twice daily (BID), starting 7 days before Cycle 1 Day 1 (C1D-7) in the experimental arm. Pembrolizumab is administered intravenously at 200 mg on Day 1 of each 21-day cycle. Gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) are administered intravenously on Days 1 and 8 of each 21-day cycle. Cisplatin is administered for a maximum of 8 cycles. Study treatment is continued according to the study protocol until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified discontinuation criteria.
• Pembrolizumab + Gemcitabine/Cisplatin (Drug): Pembrolizumab is administered intravenously at 200 mg on Day 1 of each 21-day cycle. Gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) are administered intravenously on Days 1 and 8 of each 21-day cycle. Cisplatin is administered for a maximum of 8 cycles. Study treatment is continued according to the study protocol until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified discontinuation criteria.

Primary outcomes

• Progression-Free Survival (PFS) [Up to 24 months]: Progression-free survival (PFS) is defined as the time from randomization to first documented disease progression per RECIST v1.1 criteria or death from any cause. Disease progression will be assessed by imaging according to RECIST v1.1.

Secondary outcomes

• Objective Response Rate (ORR) [Up to 24 months]: Objective response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) as assessed by investigators according to RECIST v1.1 criteria in both treatment arms.
• Disease Control Rate (DCR) [Up to 24 months]: Disease control rate is defined as the proportion of participants achieving complete response, partial response, or stable disease according to RECIST v1.1 criteria.
• Overall Survival (OS) [Up to 36 months]: Overall survival is defined as the time from randomization to death from any cause.
• Duration of Response (DoR) [Up to 24 months]: Duration of response is defined as the time from first documented objective response (CR or PR) to disease progression or death.
• Safety and Tolerability [From first dose until 30 days after last treatment]: Safety and tolerability will be assessed by incidence, severity, and type of adverse events graded according to CTCAE v5.0.

Sex: All, ages: 18 Years to any

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.

• Cun Wang, Principal investigator, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.