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).
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- フェーズ2
連絡先と場所
研究場所
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Shanghai Municipality
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Shanghai、Shanghai Municipality、中国、200032
- 募集
- Fudan University Shanghai Cancer Center
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コンタクト：
- Junjie Peng, MD, PhD
- 電話番号：86-18017317122
- メール：pengjj67@hotmail.com
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参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
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アクティブコンパレータ：従来の治療
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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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実験的：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. |
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Recurrence-Free Survival (RFS)
時間枠：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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二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Overall Survival (OS)
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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)
時間枠：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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協力者と研究者
研究記録日
主要日程の研究
研究開始 (推定)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
その他の研究ID番号
その他の研究ID番号
- LEGEND Trial
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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