Safety of Biliary Intraductal Radiofrequency Ablation in Patients With Unresectable Extrahepatic Biliary Tract Cancer (Ablatio)

Safety of Biliary Intraductal Radiofrequency Ablation in Patients With Unresectable Extrahepatic Biliary Tract Cancer Undergoing Standard of Care Chemo-immune Checkpoint Inhibitor -Therapy: a Phase II, Multicenter, Randomized and Controlled

The goal of this clinical trial is to provide evidence for the general tolerability of radiofrequency ablation (bRFA) in patients with unresectable bile duct cancer undergoing systemic palliative treatment consisting of chemotherapy (gemcitabine and cisplatin) plus durvalumab (immune-checkpoint-inhibitor, ICI). The main question it aims to answer is whether it is safe to combine chemotherapy (gemcitabine and cisplatin) and immunotherapy (durvalumab) - CICI therapy.

Participants will be assigned to either the control group or the experimental group. In the control group, the standard of care consists of endoscopy with stent placement in the bile duct and CICI, whereas in the experimental group, bRFA will be performed in addition to the standard of care. Participants will be followed up for 6 months, during the follow-up, the stage of the tumor, blood examination, the duration of the stent from the insertion until its failure, adverse events and quality of life will be examined.

Researchers will compare the standard of care alone to the experimental group to see if the additional bRFA procedure causes higher or no difference in adverse events rate.

Study Overview

• Status: Not yet recruiting
• Conditions: Bile Duct Cancer
• Intervention / Treatment: Drug: Gemcitabin, Cisplatin and Durvalumab; Procedure: Endoscopic Retrograde Cholangio-Pancreatography with stenting; Procedure: Biliary Radiofrequency Ablation

Detailed Description

Extrahepatic biliary tract cancer (EBTC) in most cases is diagnosed at an unresectable stage of disease. Standard-of-care systemic palliative treatment consists of chemotherapy (gemcitabine and cisplatin) plus durvalumab (immune-checkpoint-inhibitor, ICI). Nonetheless, overall survival remains limited at about 12.8 months. Moreover, severe adverse events can occur leading to treatment discontinuation increasing the risk of tumor progression and poor prognosis. Biliary obstruction is one of the most relevant factors for survival limiting eligibility and timing/dosing of chemo-immunotherapy. Endoscopic biliary stenting is standard to relieve jaundice, but tumor ingrowth can limit the rate and duration of success. Radiofrequency ablation (RFA) results from thermal damage created by a high-frequency alternating current released from an electrode into tissue. RFA has become a standard treatment modality in numerous indications, including the treatment of Barrett's oesophagus-related dysplasia and hepatocellular carcinoma. Intraductal biliary radiofrequency ablation (bRFA) is a relatively new method of inducing tumor necrosis via thermal energy. bRFA has been applied in patients suffering unresectable EBTC within randomized-controlled trials indicating improved stent patency as well as overall survival and progression-free survival.

The primary objective of the study is to provide evidence for the general tolerability of bRFA in patients with unresectable extrahepatic biliary tract cholangiocarcinoma undergoing CICI. It is hypothesis that bRFA is generally safe and well tolerated by patients. Primary endpoint of the study is any grade 3 or 4 adverse events leading to chemo-immune checkpoint inhibitor-therapy discontinuation up to six months after enrolment.

Eligible patients will be registered in the study database and randomized in 1:2 ratio to either the standard group (CICI with endoscopic biliary stenting) or the experimental bRFA group (CICI with endoscopic biliary stenting + bRFA).

CICI with endoscopic biliary stenting are standard of care applied commonly in both the control and the experimental group:

Endoscopic retrograde cholangiography (ERC) procedure stenting are applied at baseline and as clinically indicated. CICI cycle (Gemcitabin d1 & d8, Cisplatin d1 & d8, Durvalumab d1) are administered repeating every 21 days for a total of 8 cycles.

bRFA will be applied only to the experimental group, it is standardized as for generator settings and protocol adapting to tumor morphology using the probe at baseline, 6 and 12 weeks after study start.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Reiner Prof. Dr. med. Wiest; Phone Number: +41 31 632 59 41; Email: reiner.wiest@insel.ch
• Study Contact Backup: Name: Martin Prof. Dr. med. Berger; Phone Number: +41 31 632 41 14; Email: martin.berger@insel.ch

Study Locations

• Switzerland
  • Be
    • Bern, Be, Switzerland, 3010
      • Inselspital Bern University Hospital
      • Contact: Reiner Prof. Dr. med. Wiest; Phone Number: +41 31 632 59 41; Email: reiner.wiest@insel.ch
      • Contact: Martin Prof. Dr. med. Berger; Phone Number: +41 31 632 41 14; Email: martin.berger@insel.ch
      • Principal Investigator: Reiner Prof. Dr. med. Wiest
      • Sub-Investigator: Martin Prof. Dr. med. Berger

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

1. Male or female ≥ 18 years old
2. Histologically or cytologically confirmed diagnosis of previously untreated and unresectable*, locally advanced and/or metastatic extrahepatic biliary tract cholangiocarcinoma with obstructive jaundice (increased serum level of total bilirubin)
3. Willing and able to give written informed consent
4. ECOG performance status 0 to 1
5. Adequate bone marrow function; neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L
6. Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73m2.

Exclusion Criteria

1. Solely intrahepatic cholangiocarcinoma or mixed type liver tumors (cholangiocarcinoma with hepatocellular differentiation parts)
2. Multiple hepatic metastases with significant blockage of one or more liver segments and/or less than 50% of liver parenchyma potentially drainable on pre-intervention imaging
3. Received prior systemic treatment for unresectable and/or metastatic extrahepatic biliary tract cancer (EBTC)

4. Any autoimmune diseases including inflammatory disorders such as Crohn's disease, ulcerative colitis, Wegener granulomatosis, systemic lupus erythematosus, rheumatoid arthritis, Graves' disease. Exceptions to these criteria are as follows:

   1. Hypothyroidism following Hashimoto thyroiditis stable on hormone replacement
   2. Patients with vitiligo
   3. Any chronic skin disorders that does not require systemic treatment
5. Use of immunosuppressive medication within 3 weeks prior to the dose of durvalumab (with the exception of topical or inhaled steroids, systemic corticosteroids at physiologic doses not exceeding >10mg/d of prednisone or its equivalent.
6. Known history of HIV
7. Prior Self-Expandable Metal Stent (SEMS) placement
8. Biliary obstruction of non-tumoral etiology
9. Liver cirrhosis Child-Pugh B and C
10. Implanted with a cardiac pacemaker
11. Platelets < 100 x 109 mm3 or international normalized ratio (INR) > 1.5
12. History of organ transplantation
13. Secondary tumor (except for a tumor treated with curative intent without recurrence for more than 5 years, non-melanoma skin cancer, treated carcinoma in situs without evidence of disease)
14. Other concomitant disease or condition likely to significantly decrease life expectancy i.e., life expectancy is less than 3 months according to investigator judgement
15. Known or suspected non-compliance, drug or alcohol abuse
16. Inability to follow the procedures of the study e.g., due to language problems, psychological disorders, dementia, etc. of the participant
17. Participation in another study with investigational drug within preceding 30 days
18. Pregnancy or lactation

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
Active Comparator: Control arm; Standard of care consisting of chemotherapy + durvalumab + endoscopic stenting	Drug: Gemcitabin, Cisplatin and Durvalumab; CICI (Gemcitabin d1 & d8 Cisplatin d1 & d8, Durvalumab d1) are administered repeating every 21 days for a total of 8 cycles.; Procedure: Endoscopic Retrograde Cholangio-Pancreatography with stenting; ERCP with stenting are applied at baseline and as clinically indicated
Experimental: Biliary radiofrequency ablation; Standard of care consisting of chemotherapy + durvalumab + endoscopic stenting plus intraductal radiofrequency ablation (bRFA)	Drug: Gemcitabin, Cisplatin and Durvalumab; CICI (Gemcitabin d1 & d8 Cisplatin d1 & d8, Durvalumab d1) are administered repeating every 21 days for a total of 8 cycles.; Procedure: Endoscopic Retrograde Cholangio-Pancreatography with stenting; ERCP with stenting are applied at baseline and as clinically indicated; Procedure: Biliary Radiofrequency Ablation; Biliary Radiofrequency Ablation is applied at baseline, 6 and 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any grade 3 or 4 adverse events (AE) leading to chemo-immune checkpoint inhibitor-therapy (CICI) discontinuation up to six months after enrolment.	AEs will be assessed according to US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5). Treatment discontinuation is defined as deferral of administration by at least four weeks or a definite stop of all CICI agents.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endoscopic complications as measured by the Adverse events GastRointestEstinal Endoscopy (AGREE) criteria specifically developed for endoscopic interventions	Current guideline definitions for cholangitis, post-ERCP pancreatitis and bleeding are applied. The rate of readmissions for biliary complications will be assessed specifically by being defined as any non-elective endoscopic reintervention after the first stent placement and will be documented in terms of timing, type of intervention, hospitalization and its duration and resolution.	6 months
Progression-free survival, which is defined as the time till the progression of disease or death, whatever comes first, from the time of enrolment to the end of follow-up.		6 months
Death from any cause from the time of enrolment to the end of follow-up (overall survival).		6 months
Development of disease-specific quality-of-life as measured by the EORTC QLQ-BIL21 before every CICI cycle plus at 3 and 6 months from the start of the CICI treatment	EORTC QLQ-BIL21 (European Organisation for Research and Treatment of Cancer questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder), scores range from 0 to 100, where a lower score means a better quality of life.	6 months
Change in health-related quality-of-life at baseline, 3 and 6 months from the start of the CICI treatment as measured by the EORTC QLQ-C30	EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer questionnaire quality of life questionnaire core 30), scores range from 0 to 100, where a high scale score represents a higher response level.	6 months
Stent patency at month 3 visit and end of study visit		6 months
Number of courses of CICI applied		6 months
Total dose of CICI applied		6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Details of adverse events		6 months
Prognostic significance of response to intraductal biliary RFA by genetic tumor characterization using next-generation sequencing		6 months
Overall survival	This will be an investigator-initiated sub-study outside this protocol	6 months

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Swiss Cancer League
• Investigators: Principal Investigator: Reiner Prof. Dr. med. Wiest, Inselspital Bern University Hospital

Publications and helpful links

General Publications

• Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 3;401(10391):1853-1865. doi: 10.1016/S0140-6736(23)00727-4. Epub 2023 Apr 16. Erratum In: Lancet. 2023 Sep 16;402(10406):964.
• Rimini M, Fornaro L, Lonardi S, Niger M, Lavacchi D, Pressiani T, Lucchetti J, Giordano G, Pretta A, Tamburini E, Pirrone C, Rapposelli IG, Diana A, Martinelli E, Garajova I, Simionato F, Schirripa M, Formica V, Vivaldi C, Caliman E, Rizzato MD, Zanuso V, Nichetti F, Angotti L, Landriscina M, Scartozzi M, Ramundo M, Pastorino A, Daniele B, Cornara N, Persano M, Gusmaroli E, Cerantola R, Salani F, Ratti F, Aldrighetti L, Cascinu S, Rimassa L, Antonuzzo L, Casadei-Gardini A. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data. Liver Int. 2023 Aug;43(8):1803-1812. doi: 10.1111/liv.15641.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: February 7, 2024
• First Submitted That Met QC Criteria: February 15, 2024
• First Posted (Estimated): February 23, 2024

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Adverse events; Radiofrequency ablation; Durvalumab + chemotherapy; Chemo-immune-checkpoint-inhibitor; Extra hepatic biliary tract cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Biliary Tract Diseases; Bile Duct Diseases; Cholangiocarcinoma; Biliary Tract Neoplasms; Bile Duct Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab; Gemcitabine
• Other Study ID Numbers: 1938 Ablatio-bilica; SNCPT (Other Identifier: Portal for clinical trials in Switzerland)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This will be planned only at study completion

Drug and device information, study documents

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