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

Overview

This study aims to evaluate whether adding celecoxib to standard therapy can improve clinical outcomes in patients with advanced intrahepatic cholangiocarcinoma. The current standard treatment typically consists of immunotherapy combined with chemotherapy; however, there are significant inter-patient differences in treatment response. Therefore, this study further introduces the biomarker CK5/6 to identify patient subgroups who are more likely to benefit, thereby exploring a more precise therapeutic strategy. All eligible participants will be randomly assigned after enrollment to either the control group or the experimental group. The control group will receive the current standard first-line regimen, which includes the immunotherapy agent pembrolizumab combined with the chemotherapy agents gemcitabine and cisplatin. The experimental group will receive the same standard treatment, with the addition of oral anti-inflammatory therapy with celecoxib taken twice daily throughout the entire treatment period. Each treatment cycle lasts 21 days. During treatment, patients will undergo regular imaging assessments, laboratory tests, and safety evaluations to monitor tumor response and treatment-related adverse events, and will be followed until disease progression or discontinuation of treatment. In addition, blood and tissue samples will be collected during the study to investigate tumor biology and potential predictive biomarkers. The primary endpoints of this study include progression-free survival and objective response rate, along with concurrent safety evaluation. Adverse events potentially associated with chemotherapy, immunotherapy, and celecoxib may occur, such as bone marrow suppression, gastrointestinal reactions, immune-related inflammatory responses, as well as renal or cardiovascular toxicities. The study team will closely monitor and promptly manage all adverse events. This study aims to explore a CK5/6-based stratified personalized combination therapy strategy, with the goal of improving treatment benefit in patients with advanced intrahepatic cholangiocarcinoma and providing evidence for optimizing future clinical treatment strategies.

Interventions

• Drug Celecoxib + Pembrolizumab + Gemcitabine/Cisplatin
  Celecoxib is administered orally at a dose of 200 mg twice daily continuously in the experimental arm. Treatment is initiated at Cycle 1 Day -7 and continued until disease progression, unacceptable toxicity, or withdrawal.
• Drug Pembrolizumab + Gemcitabine/Cisplatin
  Participants receive pembrolizumab 200 mg intravenously on Day 1 of each 21-day cycle in combination with gemcitabine 1000 mg/m² and cisplatin 25 mg/m² administered intravenously on Days 1 and 8 of each cycle. Cisplatin is administered for up to 8 cycles. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

Primary outcome measures

• Progression-Free Survival (PFS) [Time frame: Up to 24 months]

Secondary outcome measures (5)

• Objective Response Rate (ORR) [Time frame: Up to 24 months]
• Disease Control Rate (DCR) [Time frame: Up to 24 months]
• Overall Survival (OS) [Time frame: Up to 36 months]
• Duration of Response (DoR) [Time frame: Up to 24 months]
• Safety and Tolerability [Time frame: From first dose until 30 days after last treatment]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Renji Hospital — Shanghai

Identifiers

NCT: NCT07632235 · 2026-086-(1)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗