Repeated Endobiliary Radiofrequency Ablation Plus Durvalumab, Gemcitabine, and Cisplatin for Unresectable Extrahepatic Cholangiocarcinoma (BRAVE)

Survival Impact of Repeated Endobiliary Radiofrequency Ablation in Patients Undergoing Durvalumab Plus Gemcitabine and Cisplatin for Extrahepatic Cholangiocarcinoma: An International Multicenter Randomized Controlled Trial (BRAVE Trial)

This international, multicenter, open-label randomized controlled trial evaluates whether repeated endobiliary radiofrequency ablation (EB-RFA) improves overall survival in patients with unresectable extrahepatic cholangiocarcinoma undergoing first-line systemic therapy with durvalumab plus gemcitabine and cisplatin (GCD). Eligible patients will be randomized 1:1 to EB-RFA with plastic stent placement or standard plastic stenting alone. A scheduled second endoscopic session will be performed at 3 months in both groups (repeat EB-RFA only in the EB-RFA arm). The primary endpoint is overall survival. Secondary endpoints include time to recurrent biliary obstruction, progression-free survival, adverse events, and technical/clinical success.

Study Overview

• Status: Recruiting
• Conditions: Extrahepatic Cholangiocarcinoma
• Intervention / Treatment: Device: Endobiliary Radiofrequency Ablation (EB-RFA); Device: Plastic Biliary Stent

Detailed Description

Extrahepatic cholangiocarcinoma (eCCA) frequently presents as unresectable disease with obstructive jaundice. Although gemcitabine, cisplatin plus durvalumab (GCD) is the global standard first-line regimen, median overall survival remains approximately one year. Endobiliary radiofrequency ablation (EB-RFA) is biologically plausible to enhance local tumor control by inducing coagulative necrosis at the biliary stricture. Retrospective studies, including a multicenter dataset from participating institutions, suggest a survival benefit of repeated EB-RFA, especially when combined with systemic therapy. However, prospective randomized evidence is lacking.

This trial (BRAVE) randomizes eligible patients to EB-RFA plus standardized endoscopic stenting or endoscopic stenting alone, followed by GCD. A planned second endoscopic session is performed at Month 3 (window 2-4 months). Additional EB-RFA sessions (≥2-month intervals) are permitted in the EB-RFA arm if imaging shows potentially ablatable lesions and clinical benefit is expected.

The study aims to determine whether repeated EB-RFA prolongs survival and improves biliary patency when integrated with modern systemic therapy.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tadahisa Inoue; Phone Number: +81561623311; Email: tinoue-tag@umin.ac.jp

Study Locations

• Japan
  • Aichi, Japan
    • Recruiting
    • Nagoya City University Hospital
  • Aichi, Japan
    • Recruiting
    • Aichi Medical University
  • Aichi, Japan
    • Recruiting
    • Nagoya City University Midori Municipal Hospital
  • Gifu, Japan
    • Recruiting
    • Gifu University Hospital
• South Korea
  • Busan, South Korea
    • Recruiting
    • Pusan National University Hospital
  • Seoul, South Korea
    • Recruiting
    • Gangnam Severance Hospital, Yonsei University College of Medicine
  • Seoul, South Korea
    • Recruiting
    • Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine
  • Seoul, South Korea
    • Recruiting
    • Severance hospital, Yonsei university college of medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Histologically or cytologically confirmed extrahepatic cholangiocarcinoma (eCCA).

Unresectable disease (unresectable due to tumor/patient factors, or patient refusal of surgery).

Biliary obstruction requiring drainage, demonstrated by abnormal cholestatic liver tests, elevated bilirubin, radiologic evidence, or existing biliary drainage.

Planned initiation of first-line systemic therapy with durvalumab + gemcitabine + cisplatin (GCD).

Age ≥18 years.

Able to provide written informed consent.

Exclusion Criteria:

Prior radiotherapy or systemic therapy for the current eCCA.

Presence of a self-expanding metal stent that cannot be endoscopically removed.

Surgically altered anatomy except for Billroth-I; prior biliary reconstruction.

History of chronic cholangitis (e.g., primary sclerosing cholangitis, IgG4-related cholangitis).

Expected survival <3 months.

Inability to insert an oral endoscope or reach the papilla.

Contraindication to endobiliary RFA.

Pregnancy or possible pregnancy.

Any condition judged unsuitable by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Endobiliary Radiofrequency Ablation + Plastic Stent + Durvalumab/Gemcitabine/Cisplatin; Participants undergo endobiliary radiofrequency ablation (EB-RFA) followed by placement of a plastic biliary stent during the index endoscopy. A scheduled second endoscopy at Month 3 (window 2-4 months) includes repeat EB-RFA and stent exchange. Additional EB-RFA sessions (≥2-month intervals) may be performed if imaging suggests a potentially ablatable residual biliary lesion. All participants receive systemic therapy with durvalumab, gemcitabine, and cisplatin according to institutional standards.	Device: Endobiliary Radiofrequency Ablation (EB-RFA); Endobiliary RFA performed using the ELRA® catheter (STARmed) with VIVA combo® generator. Recommended settings: 7-10 W, temperature control 80 °C, 120 seconds per application. Applied along the full stricture length. Repeat procedure at Month 3 (window 2-4 months). Additional sessions every ≥2 months permitted if imaging suggests ablatable residual lesion.; Device: Plastic Biliary Stent; Placement of 7Fr or 8.5Fr plastic biliary stent from hepatic side of the stenosis to the duodenum. Bilateral preferred for hilar strictures; unilateral acceptable based on drainage.
Active Comparator: Plastic Stenting + Durvalumab/Gemcitabine/Cisplatin; Participants receive standard endoscopic placement of a plastic biliary stent during the index endoscopy without EB-RFA. A scheduled elective stent exchange is performed at Month 3 (window 2-4 months). Additional elective stent exchanges every ≥2 months may be performed at the investigator's discretion. All participants receive systemic therapy with durvalumab, gemcitabine, and cisplatin according to institutional standards.	Device: Plastic Biliary Stent; Placement of 7Fr or 8.5Fr plastic biliary stent from hepatic side of the stenosis to the duodenum. Bilateral preferred for hilar strictures; unilateral acceptable based on drainage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival is defined as the time from randomization to death from any cause. Participants still alive at the last confirmed contact will be censored at that date.	From randomization until death from any cause (up to 36 months after last enrollment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Recurrent Biliary Obstruction (TRBO)	TRBO is defined as the time from stent placement to recurrent biliary obstruction (RBO).	From stent placement to RBO or censoring (up to 36 months)
Progression-Free Survival (PFS)	Progression-free survival is defined per RECIST v1.1 based on imaging performed every 2-4 months.	From randomization to radiologic progression or death (up to 36 months)
Non-RBO Survival	Time alive without recurrent biliary obstruction.	Up to 36 months
Survival Free From Late Biliary-Procedure-Related Adverse Events	Late adverse events are defined as events occurring ≥15 days after the procedure (Tokyo Criteria 2024).	Up to 36 months
Incidence and Etiology of Recurrent Biliary Obstruction (RBO)	Number and types of RBO events and their causes (sludge, tumor ingrowth/overgrowth, migration, dysfunction).	Up to 36 months
Early Adverse Events (≤14 days)	Procedure-related adverse events within 14 days, graded by Tokyo Criteria 2024.	14 days
Late Adverse Events (≥15 days)	Procedure-related adverse events occurring ≥15 days post-procedure.	Up to 36 months
Technical Success	Successful completion of the intended procedure: EB-RFA + plastic stent placement in the experimental arm Plastic stent placement in the comparator arm	At index procedure
Clinical Success	Defined as: Hyperbilirubinemia: total bilirubin reduction ≥50% or ≤1.5 mg/dL within 14 days Others: normalization of ≥2 abnormal cholestatic/hepatocellular enzymes If baseline values are normal after prior drainage, absence of re-worsening beyond abnormal thresholds.	Within 14 days after stent placement
Number of RBO Events	Count of recurrent biliary obstruction events per participant.	Up to 36 months
Number of Endoscopic Reinterventions	Total number of endoscopic procedures including therapeutic interventions required during follow-up.	Up to 36 months

Collaborators and Investigators

• Sponsor: Aichi Medical University
• Investigators: Principal Investigator: Tadahisa Inoue, Associate Professor, Department of Gastroenterology, Aichi Medical University; Principal Investigator: Jae Hee Cho, Professor, Department of Internal Medicine, Institute of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: November 16, 2025
• First Submitted That Met QC Criteria: November 16, 2025
• First Posted (Estimated): November 19, 2025

Study Record Updates

• Last Update Posted (Actual): January 13, 2026
• Last Update Submitted That Met QC Criteria: January 11, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Gemcitabine; Cisplatin; Cholangiocarcinoma; Radiofrequency Ablation; Biliary Tract Cancer; Durvalumab; Extrahepatic Cholangiocarcinoma; Endoscopic Retrograde Cholangiopancreatography (ERCP); Bile Duct Stricture; Endobiliary Radiofrequency Ablation (EB-RFA); Recurrent Biliary Obstruction (RBO)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Biliary Tract Neoplasms; Cholangiocarcinoma
• Other Study ID Numbers: BRAVE-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No