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Circulating Tumor DNA Methylation-Guided Adjuvant Therapy Decision-Making in Patients With Resectable Colorectal Cancer Liver Metastases After Resection (LEGEND)

2026. november 2. frissítette: Junjie Peng, Fudan University

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).

A tanulmány áttekintése

Állapot

Toborzás

Körülmények

Beavatkozás / kezelés

Tanulmány típusa

Beavatkozó

Beiratkozás (Becsült)

220

Fázis

  • 2. fázis

Kapcsolatok és helyek

Ez a rész a vizsgálatot végzők elérhetőségeit, valamint a vizsgálat lefolytatásának helyére vonatkozó információkat tartalmazza.

Tanulmányi helyek

  • Kína
    • Shanghai Municipality
      • Shanghai, Shanghai Municipality, Kína, 200032
        • Toborzás
        • Fudan University Shanghai Cancer Center
        • Kapcsolatba lépni:

Részvételi kritériumok

A kutatók olyan embereket keresnek, akik megfelelnek egy bizonyos leírásnak, az úgynevezett jogosultsági kritériumoknak. Néhány példa ezekre a kritériumokra a személy általános egészségi állapota vagy a korábbi kezelések.

Jogosultsági kritériumok

Tanulmányozható életkorok

18 év (Felnőtt, Idősebb felnőtt)

Egészséges önkénteseket fogad

Nem

Tanulmányozható nemek

Összes

Leírás

Inclusion Criteria:

  • 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.
  • 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.

Exclusion Criteria:

  • 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).
  • 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.

Tanulási terv

Ez a rész a vizsgálati terv részleteit tartalmazza, beleértve a vizsgálat megtervezését és a vizsgálat mérését.

Hogyan készül a tanulmány?

Tervezési részletek

  • Elsődleges cél: Kezelés
  • Kiosztás: Véletlenszerűsített
  • Beavatkozó modell: Párhuzamos hozzárendelés
  • Maszkolás: Nincs (Open Label)

Fegyverek és beavatkozások

Résztvevő csoport / kar
Beavatkozás / kezelés
Aktív összehasonlító: Hagyományos kezelés
Egyéb: Conventional Postoperative Treatment Strategy

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.
Kísérleti: ctDNA Methylation-Guided Treatment
Kombinált termék: Circulating Tumor DNA Methylation Testing

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.

Mit mér a tanulmány?

Elsődleges eredményintézkedések

Eredménymérő
Intézkedés leírása
Időkeret
Recurrence-Free Survival (RFS)
Időkeret: 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.
From randomization through the end of the two-year postoperative follow-up.

Másodlagos eredményintézkedések

Eredménymérő
Intézkedés leírása
Időkeret
Overall Survival (OS)
Időkeret: From randomization through the end of the two-year postoperative follow-up.

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.
From randomization through the end of the two-year postoperative follow-up.
Postoperative ctDNA Methylation Positivity Rate
Időkeret: One week after surgery (±3 days).

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.
One week after surgery (±3 days).
Agreement Between ctDNA Methylation Status and Imaging Findings
Időkeret: During the two-year postoperative follow-up.

Agreement between ctDNA methylation status and imaging-based no evidence of disease (NED) status.
During the two-year postoperative follow-up.
Lead Time From ctDNA Methylation Positivity to Imaging-Confirmed Recurrence
Időkeret: During the two-year postoperative follow-up.

Median time interval from ctDNA methylation positivity to subsequent imaging-confirmed recurrence.
During the two-year postoperative follow-up.
Secondary No Evidence of Disease (NED) Conversion Rate
Időkeret: During the two-year postoperative follow-up.

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.
During the two-year postoperative follow-up.
ctDNA Methylation Clearance Rate
Időkeret: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.

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.
During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
Time to ctDNA Methylation Clearance
Időkeret: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.

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.
During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
ctDNA Methylation Test Reporting Turnaround Time
Időkeret: At ctDNA methylation testing time points during the two-year postoperative follow-up.

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.
At ctDNA methylation testing time points during the two-year postoperative follow-up.
Patient-reported Quality of Life
Időkeret: During the two-year postoperative follow-up.

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.
During the two-year postoperative follow-up.
Incremental Cost-Effectiveness Ratio (ICER)
Időkeret: During the two-year postoperative follow-up.

Health economic evaluation of the ctDNA methylation-guided treatment strategy compared with conventional treatment using the incremental cost-effectiveness ratio.
During the two-year postoperative follow-up.

Együttműködők és nyomozók

Itt találhatja meg a tanulmányban érintett személyeket és szervezeteket.

Szponzor

Fudan University

Tanulmányi rekorddátumok

Ezek a dátumok nyomon követik a ClinicalTrials.gov webhelyre benyújtott vizsgálati rekordok és összefoglaló eredmények benyújtásának folyamatát. A vizsgálati feljegyzéseket és a jelentett eredményeket a Nemzeti Orvostudományi Könyvtár (NLM) felülvizsgálja, hogy megbizonyosodjon arról, hogy megfelelnek-e az adott minőség-ellenőrzési szabványoknak, mielőtt közzéteszik őket a nyilvános weboldalon.

Tanulmány főbb dátumok

Tanulmány kezdete (Becsült)

2026. november 1.

Elsődleges befejezés (Becsült)

2029. november 1.

A tanulmány befejezése (Becsült)

2031. november 1.

Tanulmányi regisztráció dátumai

Először benyújtva

2026. október 28.

Először nyújtották be, amely megfelel a minőségbiztosítási kritériumoknak

2026. november 2.

Első közzététel (Tényleges)

2026. november 4.

Tanulmányi rekordok frissítései

Utolsó frissítés közzétéve (Tényleges)

2026. november 4.

Az utolsó frissítés elküldve, amely megfelel a minőségbiztosítási kritériumoknak

2026. november 2.

Utolsó ellenőrzés

2026. november 1.

Több információ

A tanulmányhoz kapcsolódó kifejezések

Egyéb vizsgálati azonosító számok

  • LEGEND Trial

Gyógyszer- és eszközinformációk, tanulmányi dokumentumok

Egy amerikai FDA által szabályozott gyógyszerkészítményt tanulmányoz

Nem

Egy amerikai FDA által szabályozott eszközterméket tanulmányoz

Nem

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