Circulating Tumor Mitochondrial DNA (ct-mtDNA) As a Biomarker for Biliary Tract Cancer Recurrence Surveillance (CCGLC-016)

Evaluation of Circulating Tumor Mitochondrial DNA (ct-mtDNA) As a Biomarker for Minimal Residual Disease (MRD) Assessment and Recurrence Monitoring in Post-treatment Biliary Tract Cancer （BTC）

This is a prospective, observational, single-center study. The purpose of this study is to evaluate the efficacy of circulating tumor mitochondrial DNA (ct-mtDNA) in plasma as a biomarker for minimal residual disease (MRD) assessment and recurrence monitoring in patients with biliary tract cancer.

Study Overview

• Status: Recruiting
• Conditions: Biliary Tract Cancer
• Intervention / Treatment: Other: Plasma and Tumor Tissue Mitochondrial DNA (mtDNA) Mutation Analysis

Detailed Description

Biliary tract cancer (BTC) encompasses a range of malignancies including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer. While relatively rare in many high-income countries, it poses a significant health challenge in certain regions, with a rising incidence of intrahepatic cholangiocarcinoma globally. Despite recent therapeutic advancements, BTC remains an aggressive disease with a grim prognosis, characterized by a median overall survival of less than one year and a 5-year survival rate below 5%. The primary objective of this study is to evaluate the effectiveness of plasma tumor mitochondrial mutations as a biomarker for MRD assessment and recurrence monitoring in patients with BTC. The study hypothesizes that the presence and dynamics of tumor mitochondrial mutations in plasma are associated with the risk of recurrence and overall survival in BTC patients. This is a prospective, observational, single-center study conducted by the Chinese Cooperative Group of Liver Cancer (CCGLC) under the auspices of the Chinese Chapter of International Hepato-Pancreato Biliary Association. The study will involve the collection and analysis of plasma samples from patients with BTC to detect ct-mtDNA mutations before and after treatment. The primary clinical endpoint is the impact of MRD status on progression-free survival (PFS). Secondary endpoints include the influence of treatment on MRD markers, the correlation between post-treatment residual tumor molecular burden and PFS, and the ability of MRD detection to predict recurrence earlier than traditional tumor markers or imaging methods. This study seeks to contribute to the field of BTC management by providing a more precise and personalized approach to MRD assessment and recurrence monitoring. The findings have the potential to improve long-term treatment outcomes and quality of life for patients with BTC.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Ze-yang Ding, M.D.; Phone Number: +8613407156200; Email: zyding@tjh.tjmu.edu.cn
• Study Contact Backup: Name: Han Gao; Phone Number: +8617730117747; Email: gh1023606887@163.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital
      • Contact: Han Gao; Phone Number: +8617730117747; Email: gh1023606887@163.com
      • Contact: Ze yang Ding, M.D.; Phone Number: +86 13407156200; Email: zyding@tjh.tjmu.edu.cn

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The study will involve patients diagnosed with biliary tract cancer (BTC). The target population for the CCGLC-016 study consists of individuals who meet the following criteria:

Age: Participants must be 18 years of age or older. Diagnosis: Individuals must have a histologically confirmed diagnosis of BTC. Prognosis: Patients are expected to have a life expectancy of at least 12 weeks, indicating a reasonable prospect for survival following study enrollment.

Informed Consent: All participants or their legally authorized representatives must provide written informed consent. This ensures they are fully aware of the study, objectives, procedures, potential risks, and benefits, and are willing to comply with the study protocol.

Compliance: Participants must be capable of and agree to adhere to the study, visit schedule and any related proceudre.

Description

Inclusion Criteria:

• Histologically confirmed biliary tract cancer (BTC);
• Expected survival time of 12 weeks or more;
• Signed informed consent form and ability to comply with the study visits and related procedures as stipulated in the protocol.

Exclusion Criteria:

• Patients with other active tumors or severe complications;
• Insufficient tumor tissue for MRD detection.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	The primary outcome measure of this study is to evaluate the effect of minimal residual disease (MRD) status, as identified by the presence of tumor mitochondrial DNA (mtDNA) mutations in plasma, on the progression-free survival of patients after medical treatment for biliary tract cancer. Progression-free survival is defined as the time from the initiation of treatment to the first occurrence of disease progression or death due to any cause, as determined by imaging studies following RECIST 1.1 criteria.	PFS will be assessed from baseline (initiation treatment date) to the first occurrence of disease progression or death, with follow-up assessments at regular intervals up to 2 years post-treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of MRD Detection with Imaging for Early Recurrence Detection	The study will evaluate whether increases in ctDNA levels, as detected by MRD testing, precede objective disease progression detected by imaging methods, thus serving as an earlier indicator of recurrent disease.	Imaging for disease progression will be performed at 3-month intervals or as clinically indicated (up to 2 years), with ctDNA levels being monitored in parallel to determine the lead time of MRD detection over imaging.
Association of mtDNA Mutational Profile with Clinicopathological Features	An exploratory analysis will investigate whether specific mtDNA mutational profiles are associated with certain clinicopathological features of the cancer, such as tumor size, differentiation, or stage.	The association will be analyzed at baseline and throughout the study duration (up to 2 years), with specific evaluations at 3-month intervals.
Circulating tumor mtDNA (MRD Marker)	This secondary outcome measure aims to assess changes in MRD markers before treatment and at a specific time point shortly after treatment (3-7 days post-treatment). The analysis will determine the immediate impact of medical intervention on the levels of circulating tumor mtDNA, providing insights into the effectiveness of treatment in removing or reducing MRD.	Blood samples for MRD marker assessment will be collected at baseline (immediately before treatment) and at 3-7 days post-treatment.
Correlation Between Post-treatment MRD and PFS	This secondary outcome measure will analyze the relationship between the quantity of residual tumor molecular burden, as detected by MRD testing, and the length of progression-free survival. The goal is to determine if a higher molecular burden of residual disease is associated with shorter PFS.	Residual tumor molecular burden will be assessed at the time of post-treatment blood sample collection (3-7 days post-treatment), with PFS being measured from baseline to the first occurrence of disease progression or death, up to 2 years post-treatment.
Early Detection of Recurrence Through MRD Monitoring	The study will evaluate the ability of MRD detection, based on plasma tumor mtDNA mutations, to predict disease recurrence earlier than traditional tumor markers or imaging methods. This comparison will involve monitoring ctDNA levels over the two-year post-treatment period and comparing the timing of abnormal rises in ctDNA to the detection of recurrence by other means.	MRD monitoring will be conducted at regular intervals post-treatment, with the earliest detection of recurrence being the primary focus within the two-year follow-up period (e.g., every 3 months).
Comparison of MRD Detection with Tumor Markers for Early Recurrence Detection	This outcome measure will specifically compare the timing of increases in circulating tumor DNA (ctDNA) levels, as detected by MRD testing, to the rises in serum tumor markers (CEA, CA19-9) to determine which method can detect recurrence sooner.	Tumor marker levels and MRD status will be assessed at 3-month intervals post-treatment for up to two years, with the timing of abnormal rises being the critical comparison point.
Impact of Maintenance Therapy on Negative MRD Detection Rate	The study will explore whether patients receiving maintenance therapy after the initial treatment phase have a higher rate of negative MRD detection, suggesting a potential role of MRD in guiding therapeutic decisions.	Assessment of the impact of maintenance therapy on MRD detection rate will be conducted at follow-up visits where MRD testing is performed at 6-month intervals after the initial treatment phase for up to two years.

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Investigators: Study Chair: Ze-yang Ding, M.D., Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2024
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: October 8, 2024
• First Submitted That Met QC Criteria: October 20, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 26, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: recurrence; biliary tract cancer; MRD; ct-mtDNA
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Biliary Tract Neoplasms; Recurrence
• Other Study ID Numbers: TJ-IRB202407115

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No