Circulating Tumor DNA Methylation-Guided Adjuvant Therapy Decision-Making in Patients With Resectable Colorectal Cancer Liver Metastases After Resection (LEGEND)
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).
Descripción general del estudio
Estado
Estado
Condiciones
Condiciones
Intervención / Tratamiento
Intervención / Tratamiento
Tipo de estudio
Tipo de estudio
Inscripción (Estimado)
Inscripción
Fase
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Shanghai Municipality
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Shanghai, Shanghai Municipality, Porcelana, 200032
- Reclutamiento
- Fudan University Shanghai Cancer Center
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Contacto:
- Junjie Peng, MD, PhD
- Número de teléfono: 86-18017317122
- Correo electrónico: pengjj67@hotmail.com
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Criterios de participación
Criterio de elegibilidad
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Número de brazos
Armas e Intervenciones
Grupo de participantes/brazoGrupo de participantes/brazo |
Intervención / TratamientoIntervención / Tratamiento |
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Comparador activo: Tratamiento convencional
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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. |
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Experimental: ctDNA Methylation-Guided Treatment
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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. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Recurrence-Free Survival (RFS)
Periodo de tiempo: From randomization through the end of the two-year postoperative follow-up.
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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.
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Medidas de resultado secundarias
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Overall Survival (OS)
Periodo de tiempo: From randomization through the end of the two-year postoperative follow-up.
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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.
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Postoperative ctDNA Methylation Positivity Rate
Periodo de tiempo: One week after surgery (±3 days).
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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).
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Agreement Between ctDNA Methylation Status and Imaging Findings
Periodo de tiempo: During the two-year postoperative follow-up.
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Agreement between ctDNA methylation status and imaging-based no evidence of disease (NED) status. |
During the two-year postoperative follow-up.
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Lead Time From ctDNA Methylation Positivity to Imaging-Confirmed Recurrence
Periodo de tiempo: During the two-year postoperative follow-up.
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Median time interval from ctDNA methylation positivity to subsequent imaging-confirmed recurrence. |
During the two-year postoperative follow-up.
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Secondary No Evidence of Disease (NED) Conversion Rate
Periodo de tiempo: During the two-year postoperative follow-up.
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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.
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ctDNA Methylation Clearance Rate
Periodo de tiempo: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
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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.
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Time to ctDNA Methylation Clearance
Periodo de tiempo: During treatment and subsequent follow-up, through the end of the two-year postoperative follow-up.
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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.
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ctDNA Methylation Test Reporting Turnaround Time
Periodo de tiempo: At ctDNA methylation testing time points during the two-year postoperative follow-up.
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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.
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Patient-reported Quality of Life
Periodo de tiempo: During the two-year postoperative follow-up.
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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.
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Incremental Cost-Effectiveness Ratio (ICER)
Periodo de tiempo: During the two-year postoperative follow-up.
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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.
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Colaboradores e Investigadores
Patrocinador
Patrocinador
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Inicio del estudio
Finalización primaria (Estimado)
Finalización primaria
Finalización del estudio (Estimado)
Finalización del estudio
Fechas de registro del estudio
Enviado por primera vez
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Publicado por primera vez
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización publicada
Última actualización enviada que cumplió con los criterios de control de calidad
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Última verificación
Más información
Términos relacionados con este estudio
Otros números de identificación del estudio
Otros números de identificación del estudio
- LEGEND Trial
Información sobre medicamentos y dispositivos, documentos del estudio
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Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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