Predicting Non-small Cell Lung Cancer (NSCLC) Lymph Node Metastasis: Integrating Circulating Tumor DNA (ctDNA) Mutation/ Methylation Profiling With Positron Emission Tomography-computed Tomography (PET-CT) Scan

Non-small Cell Lung Cancer Clinical Trial

Official title:

Predicting NSCLC Lymph Node Metastasis: Integrating ctDNA Mutation/ Methylation Profiling With PET-CT Scan: The LUNon-invasive Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06358222
• Other study ID #: LUNon-invasive
• Status: Recruiting
• Start date: December 15, 2023
• Est. completion date: December 31, 2027

Study information

• Verified date: April 2024
• Source: Shanghai Chest Hospital
• Contact: Feng Yao, PhD
• Phone: 021-2220000
• Email: yaofeng[@]shsmu.edu.cn
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is a single center, prospective and observational study conducted in three stages to predict the NSCLC lymph node metastasis based on ctDNA/specific methylation molecular features combined with PET-CT imaging features and intervention study.

Description:

This is a prospective study conducted in three stages. The volume of blood drawn will be 30 mL each time.

Stage 1: We will enroll 200 patients diagnosed with stage I-IIIB NSCLC who are scheduled for lobectomy and systematic lymph node dissection. The prediction of lymph node metastasis will be based on preoperative blood ctDNA mutation and methylation profiling. Specifically, during this stage, we will prospectively establish ctDNA methylation signatures specifically associated with LNMs in NSCLC. These molecular profiles will be combined with PET-CT imaging. Postoperative pathological results will serve as the reference standard for comparison.

Stage 2: A certain number (depending on the Results of Stage 1) of patients requiring invasive mediastinoscopy or EBUS-TBNA, based on the clinical guidelines, will be included for blood ctDNA mutation/methylation profile (or combined PET-CT), and the detection rate of LNMs will be assessed in patients with negative preoperative blood ctDNA mutation/methylation (or combined PET-CT). The accuracy of predicting LNMs will be compared with that of patients with negative or positive preoperative blood ctDNA mutation/methylation (or combined PET-CT).

Stage 3: For patients with negative preoperative blood negative testing (ctDNA mutation/methylation profiles alone or in combination with PET-CT), systematic lymph node sampling/dissection and no lymph node dissection will be grouped and compared. Regular follow-up is performed to investigate the impact on long-term MRD negative duration and prognosis. The primary outcomes: postoperative MRD negative duration and progression-free survival (PFS); The second outcomes: Overall survival (OS).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Provision of informed consent prior to study initiation.

2. Age between 18 and 75 years.

3. Preoperative clinical evaluation indicating non-small cell lung cancer (NSCLC) stage I-IIIB (without initial treatment sought).

4. Newly treated patients who have consented to undergo surgery.

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

Exclusion Criteria:

1. Non-small cell lung cancer (NSCLC) histopathologically determined to be other than stage I-IIIB following surgical evaluation.

2. Presence of other active malignant tumor diseases.

3. Evidence of any serious or uncontrolled systemic illness, including uncontrolled hypertension and active bleeding, as assessed by the investigator, which may contribute to reluctance to participate in the trial or decrease adherence to the study regimen. Additionally, active infectious diseases such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection are grounds for exclusion.

4. History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or any indication of clinically active ILD.

5. Patients considered by the investigator to be unable to comply with the study protocol, restrictions, and requirements, or those facing circumstances at the investigator's discretion that would impede their participation in the study.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Lymphatic Metastasis
• Neoplasm Metastasis
• Non-small Cell Lung Cancer

Intervention

Procedure:
• Blood ctDNA + methylation + PET-CT and Postoperative pathology
A highly sensitive tumor-naïve MRD panel of ctDNA will be employed to detect preoperative blood. Some patients will undergo methylation profiling to prospectively establish LNMs-specific ctDNA methylation signatures.
• MRD+ methylation (or combined with PET-CT) and Invasive mediastinoscopy /EBUS-TBNA
A certain number (depending on the Results of Stage 1) of patients requiring invasive mediastinoscopy or EBUS-TBNA, based on the clinical guidelines, will be included for blood ctDNA mutation/methylation profile (or combined PET-CT), and the detection rate of LNMs will be assessed in patients with negative preoperative blood ctDNA mutation/methylation (or combined PET-CT). The accuracy of predicting LNMs will be compared with that of patients with negative or positive preoperative blood ctDNA mutation/methylation (or combined PET-CT).
• Intraoperative lymph node dissection
For patients with negative preoperative blood negative testing (ctDNA mutation/methylation profiles alone or in combination with PET-CT), systematic lymph node sampling/dissection and no lymph node dissection will be grouped and compared. Regular follow-up is performed to investigate the impact on long-term MRD negative duration and prognosis.

Locations

Country	Name	City	State
China	Shanghai Chest Hospital	ShangHai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Chest Hospital

Country where clinical trial is conducted

China, 

References & Publications (5)

Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol. 2018 Sep;15(9):577-586. doi: 10.1038/s41571-018-0058-3. — View Citation

Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endo — View Citation

Chaudhuri AA, Chabon JJ, Lovejoy AF, Newman AM, Stehr H, Azad TD, Khodadoust MS, Esfahani MS, Liu CL, Zhou L, Scherer F, Kurtz DM, Say C, Carter JN, Merriott DJ, Dudley JC, Binkley MS, Modlin L, Padda SK, Gensheimer MF, West RB, Shrager JB, Neal JW, Wakel — View Citation

Chen K, Zhao H, Shi Y, Yang F, Wang LT, Kang G, Nie Y, Wang J. Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC). Clin Cancer Res. 2019 Dec 1;25(23):7058-7067. doi: 10.1158/1078-0432.CCR-19-1213. Epub 2019 Aug 2 — View Citation

Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I; WHO Panel. The 2015 World Health Organizati — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Negative prediction value (NPV) of lymph node metastasis rates	The primary endpoint will be the negative prediction value (NPV) of LNM rates between groups using preoperative blood ctDNA/methylation alone or in combination with PET-CT. LNMs-specific ctDNA methylation signatures will be developed and the sensitivity and specificity of ctDNA mutation/methylation profiles alone or when combined with PET-CT scans for predicting LNMs will be assessed. Postoperative pathological results will serve as the reference standard for comparison.	one day for each patient
Primary	Disease-free survival (DFS)	DFS is defined as the time from surgical resection to tumor recurrence or death due to tumor progression. DFS will be compared between the ctDNA-positive group and the ctDNA-negative group. DFS will be assessed in stage 3.	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.
Primary	ctDNA-free interval (CFI)	CFI is defined as the duration between a patient's transition from ctDNA negative to ctDNA positive status.	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years.
Secondary	Overall Survival (OS)	OS is defined as the time between the start of the patient's surgical resection and any documented death from any cause. OS will be compared between ctDNA-positive and ctDNA-negative groups. OS will be assessed in stage 3.	Until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years