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

Official title

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)

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• Overall Survival (OS) [Time frame: From randomization until death from any cause (up to 36 months after last enrollment)]

Secondary outcome measures (11)

• Time to Recurrent Biliary Obstruction (TRBO) [Time frame: From stent placement to RBO or censoring (up to 36 months)]
• Progression-Free Survival (PFS) [Time frame: From randomization to radiologic progression or death (up to 36 months)]
• Non-RBO Survival [Time frame: Up to 36 months]
• Survival Free From Late Biliary-Procedure-Related Adverse Events [Time frame: Up to 36 months]
• Incidence and Etiology of Recurrent Biliary Obstruction (RBO) [Time frame: Up to 36 months]
• Early Adverse Events (≤14 days) [Time frame: 14 days]
• Late Adverse Events (≥15 days) [Time frame: Up to 36 months]
• Technical Success [Time frame: At index procedure]
• Clinical Success [Time frame: Within 14 days after stent placement]
• Number of RBO Events [Time frame: Up to 36 months]
• Number of Endoscopic Reinterventions [Time frame: Up to 36 months]

Eligibility criteria

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.

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

Japan · 4 centers

• Aichi Medical University — Aichi
• Nagoya City University Hospital — Aichi
• Nagoya City University Midori Municipal Hospital — Aichi
• Gifu University Hospital — Gifu

South Korea · 4 centers

• Pusan National University Hospital — Busan
• Gangnam Severance Hospital, Yonsei University College of Medicine — Seoul
• Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine — Seoul
• Severance Hospital, Yonsei University College of Medicine — Seoul

Identifiers

NCT: NCT07235007 · BRAVE-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗