Carcinoma, HepatocellularNCT03020342
HBV-host cfDNA as Minimal Residual Tumor Marker for HBV-related HCC
An observational study of Carcinoma, Hepatocellular, run by National Taiwan University Hospital at 1 site in Taiwan.
Trial summary
Early stage HCC is treated by curative surgical resection or by local ablation (such as radio-frequency) as the current standard of care. The complete removal of clinical visible HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or PIVKA). Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Carcinoma, Hepatocellular
- How many people
- 50 participants
- Where
- 1 siteTaiwan
- Study dates
- May 2016to Jan 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: HBV-related HCC patients that receive surgical removal of tumor.
Who may be able to join
- HBV-related HCC patients that receive surgical removal of tumor.
Who cannot join
- unsuitable for surgery.
Trial locations and contacts
1 site in 1 country.
Taiwan1 site, 1 recruiting
- Recruiting
National Taiwan University Hospital
Taipei, 100
Pei-Jer Chen, MD/PhD, +886-2-23123456 ext. 67072, peijerchen@ntu.edu.tw
Shiou-Hwei Yeh, PhD, +886-2-23123456 ext. 66644, shyeh@ntu.edu.tw
About this study
Official title: A New Biomarker for Detection of Minimal Residual Tumor in Hepatitis-B Virus Related Hepatocellular Carcinoma After Curative Therapies: The Cell-free Circulating HBV-host Chimera DNA Fragment
Early stage HCC is treated by curative surgical resection or by local ablation (such as radio-frequency) as the current standard of care. The complete removal of clinical visible HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or PIVKA). However, despite an apparent complete removal of the HCC, those post-curative patients frequently develop tumor recurrence at a rate ranging 10-50% within the first year. The high rate of early HCC recurrence indicated a minimal residual HCC after the curative therapies in a significant proportion of patients. A better and more specific biomarker for detecting the residual HCC will improve the patients' prognosis prediction and therapeutic plan.
To detect the minimal residual HCC, a biomarker unique to the tumor is needed. Currently, the cell-free circulating DNA carrying tumor-specific somatic mutations has been advocated as a promising one. It has been applied to investigate the tumor responses or resistances to cancer therapy. However, currently it is restricted to detect or follow only large advanced cancer, because of the difficulty in separating or enriching the cfDNA with tumor-specific mutations from the cfDNA from normal cells. In this project, the investigators proposed that one class of somatic mutation in HBV-related HCC, namely the insertion mutagenesis by integrated HBV DNA, could be adopted to circumvent this difficulty. HBV DNA integration has been found in the chromosomes of about 90% of HBV-related HCC and the integration site is unique to individual HCC. The HBV-host junction DNA fragment from one HCC is therefore a tumor-specific biomarker. Such fragments can be released into the circulation as cell-free circulating DNAs, and the detection of the HBV-host chimera DNAs in the circulation is a reliable evidence for the presence of the tumor in the patient. Therefore the cf circulating HBV-host chimera DNA is proposed to assay any minimal residual HCC after curative therapies.
Read the detailed description
Development stages:
Stage I: Identification of integrated HBV DNA sites in HBV-related HCC tissues. the investigators will develop either HBV-specific inverse PCRs or capture-sequencing protocols to identify HBV integrations sites in the tumor chromosomes. The viral-host junction sequences of individual HCC identified and used as the template for developing assays for detecting the same HBV-host chimera DNA fragment in the circulation.
Stage II: New platforms to accurately detect or even quantitate the circulating vh-chimera DNA fragment.
These tumor-specific vh-chimera DNA will only represent a tiny fraction of total cfDNAs. However, as these sequences of the tumor-specific vh-chimera DNA have been known from stage 1, the investigators may develop better and more specific assays for quantitation.
Stage III: Assays for cell-free tumor specific vh-chimera DNA applied to the blood samples from post-curative HCC patients.
To demonstrate the efficacy of these assays, blood samples obtained at 4 weeks after curative therapies from 50 HBV-related HCC patients, and tested for the presence of cf tumor-specific vh-chimera DNAs. The presence or absence of such vh-chimera DNA will be correlated with the early HCC recurrence within the first year to determine any clinical significance. There will be one blood sampling at the time of HCC recurrence.
Sample collection In stage I and II, the investigators will set up methods for chimera DNA identification and quantification, which need tumor samples to support the development and evaluation of the feasibility for each assay. Therefore, the investigators will apply the approval for use the tissues from the Taiwan Liver Cancer Network (TLCN), including 20 pairs of HBV-related male HCC, 20 pairs of HBV-related female HCC (for positive control), 20 pairs of HCV related male HCC, 20 pairs of HCV related female HCC (for negative control), 20 pairs of HBV- and HCV-related male HCC, and 20 pairs of HBV- and HCV-related female HCC (to see if vh-chimera DNA is also applicable for HBV- and HCV-related HCC). Both the genomic DNA and RNA will be applied for these 120 patients in total. Genomic DNA will be used in assay development, including identification, detection and quantification; whereas RNA will be used in validation of the insertional mutagenic RNA transcripts, which will provide supporting evidence for tumor specific integration from transcription level.
In stage III, the investigators will investigate whether there is any correlation between tumor-specific vh-chimera DNA level and recurrence-free survival using the assays the investigators developed in stage I and II. Therefore, the investigators will collect the Tumor (T) and non-Tumor (NT) tissue pairs from 50 HBV-related HCC patients that receive surgical removal of tumor, and also the peripheral blood at 4w after surgery. T and NT tissues are for vh-chimera DNA identification, peripheral blood will be used for vh-chimera DNA detection and quantification. On the other hand, clinical information including tumor size, tumor grade, serum markers from routine liver function test (ALT, AST), current HCC marker (AFP), and recurrence-free survival time will be collected for correlation study. All data will be stored in computer with password protection.
- Conditions
- Carcinoma, Hepatocellular
- Keywords
- HCC, chimera DNA, circulating DNA, biomarker
- Medical subject headings
- Carcinoma, Hepatocellular
What is being measured
The primary outcome is the main question the study is designed to answer.
vh-chimera DNA
Detection of the HBV-host chimera DNA in blood sample.----- one blood sampling at the time of HCC recurrence.
Measured: week 4 after surgery.
Secondary outcomes (3)
Tumor size (measured in the longest dimension in cm)
clinical information about HCC recurrence. detection by CT or MRI.
Measured: after medical imaging or pathology report completion, up to 2 weeks.
tumor grade (Grades I-IV)
clinical information about HCC recurrence. detection by CT or MRI.
Measured: after medical imaging or pathology report completion, up to 2 weeks.
recurrence-free survival time ----measurement in weeks
clinical information about HCC recurrence.
Measured: from the date of surgery until the date of first documented HCC recurrence or date of death from any cause, whichever came first, assessed up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2017 (estimated)
- Study startMay 2016
- Primary completionJan 2019 (estimated)
- Study completionJan 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Carcinoma, HepatocellularStudies of the same condition, open and under way.
- More trials run by National Taiwan University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Taiwan University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Pei-Jer Chen, MD-PhD, Principal investigator, National Taiwan University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03020342
- Sponsor's protocol ID
- 201510056RINA
- Status last verified
- Jan 2017
- First submitted
- 22 Jun 2016
- Last updated
- 13 Jan 2017
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A New Biomarker for Detection of Minimal Residual Tumor in Hepatitis-B Virus Related Hepatocellular Carcinoma After Curative Therapies: The Cell-free Circulating HBV-host Chimera DNA Fragment
- ClinicalTrials.gov ID
- NCT03020342
- Acronym / sponsor ID
- 201510056RINA
- Conditions
- Carcinoma, Hepatocellular
- Keywords
- HCC, chimera DNA, circulating DNA, biomarker
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- National Taiwan University HospitalUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- Jan 2019 (estimated)
- Study completion
- Jan 2019 (estimated)
- First posted
- 13 Jan 2017 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Early stage HCC is treated by curative surgical resection or by local ablation (such as radio-frequency) as the current standard of care. The complete removal of clinical visible HCC is then confirmed by imaging by MRI or CT, or by a decline of tumor marker (AFP or PIVKA). However, despite an apparent complete removal of the HCC, those post-curative patients frequently develop tumor recurrence at a rate ranging 10-50% within the first year. The high rate of early HCC recurrence indicated a minimal residual HCC after the curative therapies in a significant proportion of patients. A better and more specific biomarker for detecting the residual HCC will improve the patients' prognosis prediction and therapeutic plan.
To detect the minimal residual HCC, a biomarker unique to the tumor is needed. Currently, the cell-free circulating DNA carrying tumor-specific somatic mutations has been advocated as a promising one. It has been applied to investigate the tumor responses or resistances to cancer therapy. However, currently it is restricted to detect or follow only large advanced cancer, because of the difficulty in separating or enriching the cfDNA with tumor-specific mutations from the cfDNA from normal cells. In this project, the investigators proposed that one class of somatic mutation in HBV-related HCC, namely the insertion mutagenesis by integrated HBV DNA, could be adopted to circumvent this difficulty. HBV DNA integration has been found in the chromosomes of about 90% of HBV-related HCC and the integration site is unique to individual HCC. The HBV-host junction DNA fragment from one HCC is therefore a tumor-specific biomarker. Such fragments can be released into the circulation as cell-free circulating DNAs, and the detection of the HBV-host chimera DNAs in the circulation is a reliable evidence for the presence of the tumor in the patient. Therefore the cf circulating HBV-host chimera DNA is proposed to assay any minimal residual HCC after curative therapies.
Detailed description
Development stages:
Stage I: Identification of integrated HBV DNA sites in HBV-related HCC tissues. the investigators will develop either HBV-specific inverse PCRs or capture-sequencing protocols to identify HBV integrations sites in the tumor chromosomes. The viral-host junction sequences of individual HCC identified and used as the template for developing assays for detecting the same HBV-host chimera DNA fragment in the circulation.
Stage II: New platforms to accurately detect or even quantitate the circulating vh-chimera DNA fragment.
These tumor-specific vh-chimera DNA will only represent a tiny fraction of total cfDNAs. However, as these sequences of the tumor-specific vh-chimera DNA have been known from stage 1, the investigators may develop better and more specific assays for quantitation.
Stage III: Assays for cell-free tumor specific vh-chimera DNA applied to the blood samples from post-curative HCC patients.
To demonstrate the efficacy of these assays, blood samples obtained at 4 weeks after curative therapies from 50 HBV-related HCC patients, and tested for the presence of cf tumor-specific vh-chimera DNAs. The presence or absence of such vh-chimera DNA will be correlated with the early HCC recurrence within the first year to determine any clinical significance. There will be one blood sampling at the time of HCC recurrence.
Sample collection In stage I and II, the investigators will set up methods for chimera DNA identification and quantification, which need tumor samples to support the development and evaluation of the feasibility for each assay. Therefore, the investigators will apply the approval for use the tissues from the Taiwan Liver Cancer Network (TLCN), including 20 pairs of HBV-related male HCC, 20 pairs of HBV-related female HCC (for positive control), 20 pairs of HCV related male HCC, 20 pairs of HCV related female HCC (for negative control), 20 pairs of HBV- and HCV-related male HCC, and 20 pairs of HBV- and HCV-related female HCC (to see if vh-chimera DNA is also applicable for HBV- and HCV-related HCC). Both the genomic DNA and RNA will be applied for these 120 patients in total. Genomic DNA will be used in assay development, including identification, detection and quantification; whereas RNA will be used in validation of the insertional mutagenic RNA transcripts, which will provide supporting evidence for tumor specific integration from transcription level.
In stage III, the investigators will investigate whether there is any correlation between tumor-specific vh-chimera DNA level and recurrence-free survival using the assays the investigators developed in stage I and II. Therefore, the investigators will collect the Tumor (T) and non-Tumor (NT) tissue pairs from 50 HBV-related HCC patients that receive surgical removal of tumor, and also the peripheral blood at 4w after surgery. T and NT tissues are for vh-chimera DNA identification, peripheral blood will be used for vh-chimera DNA detection and quantification. On the other hand, clinical information including tumor size, tumor grade, serum markers from routine liver function test (ALT, AST), current HCC marker (AFP), and recurrence-free survival time will be collected for correlation study. All data will be stored in computer with password protection.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- HBV-related HCC patients that receive surgical removal of tumor.
Key inclusion criteria (1 listed)
- HBV-related HCC patients that receive surgical removal of tumor.
Key exclusion criteria (1 listed)
- unsuitable for surgery.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
vh-chimera DNA
Time frame: week 4 after surgery.
Detection of the HBV-host chimera DNA in blood sample.----- one blood sampling at the time of HCC recurrence.
3 secondary outcomes
Tumor size (measured in the longest dimension in cm)
Time frame: after medical imaging or pathology report completion, up to 2 weeks.
tumor grade (Grades I-IV)
Time frame: after medical imaging or pathology report completion, up to 2 weeks.
recurrence-free survival time ----measurement in weeks
Time frame: from the date of surgery until the date of first documented HCC recurrence or date of death from any cause, whichever came first, assessed up to 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2017.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pei-Jer Chen, MD-PhD principal investigator
National Taiwan University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Carcinoma, Hepatocellular, run by National Taiwan University Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Pei-Jer Chen, MD-PhD (+886-2-23123456 ext. 67072, peijerchen@ntu.edu.tw), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
vh-chimera DNA (time frame: week 4 after surgery.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2017.