Colorectal Cancer Liver Metastases (CRLM)Phase 2LEGENDNCT07917104
Circulating Tumor DNA Methylation-Guided Adjuvant Therapy Decision-Making in Patients With Resectable Colorectal Cancer Liver Metastases After Resection
A Phase 2 study testing Circulating Tumor DNA Methylation Testing and Conventional Postoperative Treatment Strategy in people with Colorectal Cancer Liver Metastases (CRLM) and ctDNA, run by Fudan University at 1 site in China.
Trial summary
This is a prospective, randomized, controlled, multicenter phase II trial evaluating whether circulating tumor DNA (ctDNA) methylation-guided adjuvant therapy improves outcomes after R0 resection of colorectal cancer liver metastases (CRLM). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Colorectal Cancer Liver Metastases (CRLM), ctDNA
- What is being tested?
- Circulating Tumor DNA Methylation Testing and Conventional Postoperative Treatment Strategy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 220 participants
- Where
- 1 siteChina
- Study dates
- Nov 2026to Nov 2031
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 to 75 years, regardless of sex.
- Histopathologically confirmed colorectal adenocarcinoma with liver metastases confirmed by contrast-enhanced CT or MRI.
- Liver metastases assessed as resectable by a multidisciplinary team, with R0 resection completed. Simultaneous or staged resection of the primary tumor and liver metastases is permitted. R0 resection is defined as negative surgical margins with no macroscopic or microscopic residual disease.
- No residual disease on contrast-enhanced CT or MRI performed within one month after surgery, confirming no evidence of disease (NED).
- No previous systemic anticancer treatment for metastatic disease, including chemotherapy, targeted therapy, or immunotherapy. If prior neoadjuvant or adjuvant chemotherapy was administered, the interval between the last dose and the diagnosis of liver metastases must be at least six months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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- Postoperative peripheral blood samples (two 10-mL tubes) can be obtained for ctDNA methylation testing.
- Able to understand and voluntarily sign written informed consent.
- Willing and able to comply with the follow-up schedule specified in the study protocol.
Who cannot join
- Non-adenocarcinoma histology, such as neuroendocrine tumor, squamous cell carcinoma, or adenosquamous carcinoma.
- Extrahepatic metastases, including metastases to the lungs, bones, brain, peritoneum, or distant lymph nodes.
- Previous local treatment of the primary tumor or metastatic lesions, such as radiofrequency ablation or radiotherapy, without complete tumor eradication.
- Residual disease confirmed by imaging one month after surgery, indicating that NED has not been achieved.
- Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status and considered suitable for immunotherapy by the investigator.
- Severe hepatic or renal dysfunction (ALT/AST >3 times the upper limit of normal [ULN], total bilirubin >1.5 times ULN, or creatinine >1.5 times ULN), or impaired bone marrow function (white blood cell count <3.0 × 10^9/L, neutrophil count <1.5 × 10^9/L, platelet count <75 × 10^9/L, or hemoglobin <90 g/L).
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- Uncontrolled severe hypertension (persistent systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg), severe infection, active hepatitis B (HBV DNA >1000 copies/mL), hepatitis C (positive HCV RNA), or human immunodeficiency virus infection.
- History of serious cardiovascular or cerebrovascular disease, including New York Heart Association (NYHA) functional class III or higher, myocardial infarction or unstable angina within the past six months, or uncontrolled arrhythmia.
- Known allergy or contraindication to chemotherapy agents potentially used in the study (oxaliplatin, irinotecan, 5-fluorouracil, or capecitabine) or targeted agents (cetuximab beta or bevacizumab).
- Other malignancies, except non-melanoma skin cancer or cervical carcinoma in situ that has been treated curatively with no evidence of recurrence for more than five years.
- Pregnancy or breastfeeding, or refusal by participants of reproductive potential to use effective contraception during the study.
- History of alcohol abuse or drug abuse.
- Cognitive impairment or severe psychiatric illness that prevents understanding of or compliance with study requirements.
- Any other clinical or laboratory condition that, in the investigator's opinion, makes the participant unsuitable for this study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site, 1 recruiting
- Recruiting
Fudan University Shanghai Cancer Center
Shanghai, Shanghai Municipality, 200032
Junjie Peng, MD, PhD, 86-18017317122, pengjj67@hotmail.com
About this study
Official title: Circulating Tumor DNA Methylation-Guided Adjuvant Therapy Decision-Making in Patients With Resectable Colorectal Cancer Liver Metastases After Resection: A Prospective, Randomized Controlled, Multicenter Phase II Clinical Trial (LEGEND Trial)
This is a prospective, randomized, controlled, multicenter phase II trial evaluating whether circulating tumor DNA (ctDNA) methylation-guided adjuvant therapy improves outcomes after R0 resection of colorectal cancer liver metastases (CRLM). Patients are randomized 1:1 to a ctDNA-guided arm or a conventional-treatment arm, stratified by RAS/BRAF status and primary tumor sidedness.
In the ctDNA-guided arm, postoperative plasma ctDNA methylation testing (mqMSP, 10 tumor-specific methylation markers, 3-day turnaround) is performed at week 1 after surgery. ctDNA-negative patients enter surveillance with ctDNA and imaging every 3 months, with chemotherapy ± targeted therapy triggered upon ctDNA positivity; ctDNA-positive patients start chemotherapy ± targeted therapy, with treatment paused upon ctDNA clearance and restarted upon recurrence, for a maximum cumulative treatment duration of 6 months and no more than 2 restarts. In the conventional arm, investigators choose adjuvant therapy per NCCN/CSCO guidelines, and blood samples are collected but ctDNA results are blinded and not used for treatment decisions.
The primary endpoint is recurrence-free survival (RFS). Secondary endpoints include overall survival, ctDNA positivity rate and its correlation with clinicopathological features, concordance between ctDNA and imaging, lead time of ctDNA in detecting recurrence, secondary NED conversion rate, feasibility and safety of ctDNA-guided dynamic treatment adjustment, ctDNA clearance rate, report turnaround time, patient-reported outcomes (EORTC QLQ-C30/QLQ-CR29), and health economic evaluation (ICER).
- Conditions
- Colorectal Cancer Liver Metastases (CRLM), ctDNA
- Being tested
- Circulating Tumor DNA Methylation Testing, Conventional Postoperative Treatment Strategy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Circulating Tumor DNA Methylation TestingCombination product
Participants undergo postoperative plasma ctDNA methylation testing after R0 resection. ctDNA-negative participants enter surveillance without adjuvant chemotherapy, with ctDNA testing and imaging every 3 months; chemotherapy ± targeted therapy is triggered upon ctDNA positivity. ctDNA-positive participants start chemotherapy ± targeted therapy (FOLFOX or FOLFIRI plus cetuximab for RAS/BRAF wild-type; plus bevacizumab for RAS/BRAF mutant), with ctDNA testing and imaging every 2 months during treatment. Treatment is paused upon ctDNA clearance and restarted upon ctDNA re-positivity, with a maximum cumulative treatment duration of 6 months and no more than 2 restarts. Imaging-confirmed disease progression leads to discontinuation of protocol-directed treatment.
Conventional Postoperative Treatment StrategyOther
Participants receive adjuvant therapy as determined by the investigator according to NCCN/CSCO guidelines and clinical practice, based on clinicopathological risk factors such as CRS score, primary tumor lymph node status, CEA level, surgical margin, and performance status. Blood samples are collected at baseline (approximately one week after surgery or before adjuvant therapy) and after completion of adjuvant therapy (within 4 weeks of the last chemotherapy dose, or at week 12 postoperatively for those not receiving chemotherapy), and are centrally tested for ctDNA methylation with results blinded and not used to guide treatment.
| Study group | Role | What they receive |
|---|---|---|
| ctDNA Methylation-Guided Treatment | Experimental | Not described Receives: Combination Product: Circulating Tumor DNA Methylation Testing |
| Conventional Treatment | Active comparator | Not described Receives: Other: Conventional Postoperative Treatment Strategy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recurrence-Free Survival (RFS)
Time from randomization to the first imaging-confirmed local recurrence or distant metastasis, assessed according to RECIST 1.1, or death from any cause, whichever occurs first. Participants without an event at the last follow-up will be censored at that date. RFS will be compared between the ctDNA methylation-guided treatment group and the conventional treatment group.
Measured: From randomization through the end of the two-year postoperative follow-up.
Secondary outcomes (10)
Overall Survival (OS)
Time from randomization to death from any cause. Participants who are alive at the last follow-up will be censored at that date. OS will be compared between the two treatment groups.
Measured: From randomization through the end of the two-year postoperative follow-up.
Postoperative ctDNA Methylation Positivity Rate
Proportion of all enrolled participants with positive ctDNA methylation results one week after surgery. Associations between postoperative ctDNA methylation status and clinicopathological characteristics will also be assessed.
Measured: One week after surgery (±3 days).
Agreement Between ctDNA Methylation Status and Imaging Findings
Agreement between ctDNA methylation status and imaging-based no evidence of disease (NED) status.
Measured: During the two-year postoperative follow-up.
Lead Time From ctDNA Methylation Positivity to Imaging-Confirmed Recurrence
Median time interval from ctDNA methylation positivity to subsequent imaging-confirmed recurrence.
Measured: During the two-year postoperative follow-up.
Secondary No Evidence of Disease (NED) Conversion Rate
Proportion of all participants with recurrence who receive curative-intent local treatment after recurrence and achieve NED. This proportion will be compared between the two treatment groups.
Measured: During the two-year postoperative follow-up.
ctDNA Methylation Clearance Rate
Proportion of participants in the ctDNA methylation-guided treatment group with initially positive ctDNA results who become ctDNA negative after treatment. The association between ctDNA clearance and RFS will be explored.
Measured: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
Time to ctDNA Methylation Clearance
Median time to conversion from ctDNA positivity to negativity after treatment in participants with initially positive ctDNA results in the ctDNA methylation-guided treatment group.
Measured: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
ctDNA Methylation Test Reporting Turnaround Time
Turnaround time for reporting ctDNA methylation test results, with a target of no more than five working days, and its impact on the timeliness of clinical decision-making.
Measured: At ctDNA methylation testing time points during the two-year postoperative follow-up.
Patient-reported Quality of Life
Patient-reported quality of life assessed using the EORTC QLQ-C30 questionnaire. Quality of life will be compared between the ctDNA methylation-guided treatment group and the conventional treatment group.
Measured: During the two-year postoperative follow-up.
Incremental Cost-Effectiveness Ratio (ICER)
Health economic evaluation of the ctDNA methylation-guided treatment strategy compared with conventional treatment using the incremental cost-effectiveness ratio.
Measured: During the two-year postoperative follow-up.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2026
- Study startNov 2026 (estimated)
- Primary completionNov 2029 (estimated)
- Study completionNov 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colorectal Cancer Liver Metastases (CRLM)Studies of the same condition, open and under way.
- More trials run by Fudan UniversityThe 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
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 220 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fudan University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Junjie Peng, Fudan University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07917104
- Sponsor's protocol ID
- LEGEND Trial
- Acronym
- LEGEND
- Status last verified
- Nov 2026
- First submitted
- 28 Oct 2026
- Last updated
- 4 Nov 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Circulating Tumor DNA Methylation-Guided Adjuvant Therapy Decision-Making in Patients With Resectable Colorectal Cancer Liver Metastases After Resection: A Prospective, Randomized Controlled, Multicenter Phase II Clinical Trial (LEGEND Trial)
- ClinicalTrials.gov ID
- NCT07917104
- Acronym / sponsor ID
- LEGEND / LEGEND Trial
- Conditions
- Colorectal Cancer Liver Metastases (CRLM), ctDNA
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 220 participants (estimated)
- Lead sponsor
- Fudan UniversityUniversity, hospital or other
- Study start
- Nov 2026 (estimated)
- Primary completion
- Nov 2029 (estimated)
- Study completion
- Nov 2031 (estimated)
- First posted
- 4 Nov 2026 (actual)
- 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.
This is a prospective, randomized, controlled, multicenter phase II trial evaluating whether circulating tumor DNA (ctDNA) methylation-guided adjuvant therapy improves outcomes after R0 resection of colorectal cancer liver metastases (CRLM). Patients are randomized 1:1 to a ctDNA-guided arm or a conventional-treatment arm, stratified by RAS/BRAF status and primary tumor sidedness.
In the ctDNA-guided arm, postoperative plasma ctDNA methylation testing (mqMSP, 10 tumor-specific methylation markers, 3-day turnaround) is performed at week 1 after surgery. ctDNA-negative patients enter surveillance with ctDNA and imaging every 3 months, with chemotherapy ± targeted therapy triggered upon ctDNA positivity; ctDNA-positive patients start chemotherapy ± targeted therapy, with treatment paused upon ctDNA clearance and restarted upon recurrence, for a maximum cumulative treatment duration of 6 months and no more than 2 restarts. In the conventional arm, investigators choose adjuvant therapy per NCCN/CSCO guidelines, and blood samples are collected but ctDNA results are blinded and not used for treatment decisions.
The primary endpoint is recurrence-free survival (RFS). Secondary endpoints include overall survival, ctDNA positivity rate and its correlation with clinicopathological features, concordance between ctDNA and imaging, lead time of ctDNA in detecting recurrence, secondary NED conversion rate, feasibility and safety of ctDNA-guided dynamic treatment adjustment, ctDNA clearance rate, report turnaround time, patient-reported outcomes (EORTC QLQ-C30/QLQ-CR29), and health economic evaluation (ICER).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ctDNA Methylation-Guided Treatment | Experimental | Combination Product: Circulating Tumor DNA Methylation Testing |
| Conventional Treatment | Active comparator | Other: Conventional Postoperative Treatment Strategy |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Age 18 to 75 years, regardless of sex.
- Histopathologically confirmed colorectal adenocarcinoma with liver metastases confirmed by contrast-enhanced CT or MRI.
- Liver metastases assessed as resectable by a multidisciplinary team, with R0 resection completed. Simultaneous or staged resection of the primary tumor and liver metastases is permitted. R0 resection is defined as negative surgical margins with no macroscopic or microscopic residual disease.
- No residual disease on contrast-enhanced CT or MRI performed within one month after surgery, confirming no evidence of disease (NED).
- No previous systemic anticancer treatment for metastatic disease, including chemotherapy, targeted therapy, or immunotherapy. If prior neoadjuvant or adjuvant chemotherapy was administered, the interval between the last dose and the diagnosis of liver metastases must be at least six months.
Key exclusion criteria (14 listed)
- Non-adenocarcinoma histology, such as neuroendocrine tumor, squamous cell carcinoma, or adenosquamous carcinoma.
- Extrahepatic metastases, including metastases to the lungs, bones, brain, peritoneum, or distant lymph nodes.
- Previous local treatment of the primary tumor or metastatic lesions, such as radiofrequency ablation or radiotherapy, without complete tumor eradication.
- Residual disease confirmed by imaging one month after surgery, indicating that NED has not been achieved.
- Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status and considered suitable for immunotherapy by the investigator.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Circulating Tumor DNA Methylation TestingParticipants undergo postoperative plasma ctDNA methylation testing after R0 resection. ctDNA-negative participants enter surveillance without adjuvant chemotherapy, with ctDNA testing and imaging every 3 months; chemotherapy ± targeted therapy is triggered upon ctDNA positivity. ctDNA-positive participants start chemotherapy ± targeted therapy (FOLFOX or FOLFIRI plus cetuximab for RAS/BRAF wild-type; plus bevacizumab for RAS/BRAF mutant), with ctDNA testing and imaging every 2 months during treatment. Treatment is paused upon ctDNA clearance and restarted upon ctDNA re-positivity, with a maximum cumulative treatment duration of 6 months and no more than 2 restarts. Imaging-confirmed disease progression leads to discontinuation of protocol-directed treatment. | Combination product | ctDNA Methylation-Guided Treatment |
| Conventional Postoperative Treatment StrategyParticipants receive adjuvant therapy as determined by the investigator according to NCCN/CSCO guidelines and clinical practice, based on clinicopathological risk factors such as CRS score, primary tumor lymph node status, CEA level, surgical margin, and performance status. Blood samples are collected at baseline (approximately one week after surgery or before adjuvant therapy) and after completion of adjuvant therapy (within 4 weeks of the last chemotherapy dose, or at week 12 postoperatively for those not receiving chemotherapy), and are centrally tested for ctDNA methylation with results blinded and not used to guide treatment. | Other | Conventional Treatment |
Primary outcome
Recurrence-Free Survival (RFS)
Time frame: From randomization through the end of the two-year postoperative follow-up.
Time from randomization to the first imaging-confirmed local recurrence or distant metastasis, assessed according to RECIST 1.1, or death from any cause, whichever occurs first. Participants without an event at the last follow-up will be censored at that date. RFS will be compared between the ctDNA methylation-guided treatment group and the conventional treatment group.
10 secondary outcomes
Overall Survival (OS)
Time frame: From randomization through the end of the two-year postoperative follow-up.
Postoperative ctDNA Methylation Positivity Rate
Time frame: One week after surgery (±3 days).
Agreement Between ctDNA Methylation Status and Imaging Findings
Time frame: During the two-year postoperative follow-up.
Lead Time From ctDNA Methylation Positivity to Imaging-Confirmed Recurrence
Time frame: During the two-year postoperative follow-up.
Secondary No Evidence of Disease (NED) Conversion Rate
Time frame: During the two-year postoperative follow-up.
ctDNA Methylation Clearance Rate
Time frame: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
Time to ctDNA Methylation Clearance
Time frame: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
ctDNA Methylation Test Reporting Turnaround Time
Time frame: At ctDNA methylation testing time points during the two-year postoperative follow-up.
Patient-reported Quality of Life
Time frame: During the two-year postoperative follow-up.
Incremental Cost-Effectiveness Ratio (ICER)
Time frame: During the two-year postoperative follow-up.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2026.
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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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Circulating Tumor DNA Methylation Testing and Conventional Postoperative Treatment Strategy in people with Colorectal Cancer Liver Metastases (CRLM) and ctDNA, run by Fudan University at 1 site in China.
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 9 inclusion and 14 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: looking for participants now, as of the sponsor's last update on 4 Nov 2026. 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 China. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recurrence-Free Survival (RFS) (time frame: From randomization through the end of the two-year postoperative follow-up.). 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 4 Nov 2026.