Dynamic ctDNA-Guided Adjuvant Therapy in cStage III and IVA Gastric or Gastroesophageal Junction Adenocarcinoma

Dynamic Circulating Tumor DNA-Guided Adjuvant Therapy in cStage III and IVA Gastric or Gastroesophageal Junction Adenocarcinoma：A Phase 2 Clinical Trial

This is a single-center, prospective, exploratory study evaluating the use of dynamic circulating tumor DNA (ctDNA) monitoring in the postoperative adjuvant treatment setting for patients with stage III or stage IVA gastric or gastroesophageal junction adenocarcinoma.

After curative-intent surgery, patients remain at risk of disease recurrence. Postoperative treatment decisions are currently based on clinicopathological factors, which may not fully reflect minimal residual disease. ctDNA is a blood-based biomarker that can detect tumor-derived DNA fragments and may provide additional information on recurrence risk.

In this study, ctDNA will be assessed at predefined perioperative and postoperative time points using peripheral blood samples. The primary objective is to evaluate 1-year disease-free survival. Secondary objectives include survival outcomes, safety, and longitudinal changes in ctDNA status. The findings of this exploratory study may inform future research on ctDNA-guided postoperative management in gastric cancer.

This is a single-center, prospective, exploratory study designed to evaluate the feasibility and clinical value of using dynamic circulating tumor DNA (ctDNA) testing to guide postoperative adjuvant treatment in patients with stage III or stage IVA gastric or gastroesophageal junction adenocarcinoma.

After curative-intent surgery, patients remain at risk of disease recurrence. Currently, postoperative adjuvant treatment decisions are mainly based on clinical and pathological factors, which may not fully reflect the presence of minimal residual disease. ctDNA is a blood-based biomarker that can detect small amounts of tumor-derived DNA and may provide additional information about recurrence risk after surgery.

In this study, ctDNA will be dynamically assessed at predefined perioperative and postoperative time points using peripheral blood samples. The study aims to explore the association between postoperative ctDNA status and disease outcomes, as well as the potential role of ctDNA monitoring in postoperative adjuvant treatment management.

The primary objective of this study is to evaluate disease-free survival at 1 year. Secondary objectives include assessment of survival outcomes, safety, and changes in ctDNA status over time. The results of this exploratory study are expected to provide preliminary evidence to support further clinical research on ctDNA-guided adjuvant treatment strategies in gastric cancer.

Inclusion Criteria:

1. Voluntarily participate in the study; fully understand the study and sign the written informed consent form (ICF); be willing and able to comply with all study procedures.

2. Male or female patients aged ≥18 years and ≤75 years at the time of signing the ICF.

3. Histologically confirmed, previously untreated gastric cancer or gastroesophageal junction (GEJ) cancer, with adenocarcinoma as the predominant histology. For GEJ cancer, only Siewert type III and Siewert type II tumors not requiring thoracotomy are eligible.

4. Clinically confirmed stage III or stage IVA disease without distant metastasis, as assessed by the treating physician prior to enrollment.

5. HER2-negative disease.

6. Adequate cardiac function and deemed suitable for curative-intent surgical resection. Patients with ischemic heart disease, valvular disease, or other significant cardiac conditions should undergo preoperative evaluation by a cardiologist if clinically indicated.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to enrollment.

8. Estimated life expectancy of at least 6 months.

9. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core antibody (HBcAb). If HBsAg-positive or HBcAb-positive, hepatitis B virus DNA (HBV-DNA) must be <1000 copies/mL, <200 IU/mL, or below the upper limit of normal (ULN) of the study center.

10. Negative hepatitis C virus (HCV) antibody.

11. Adequate organ function, defined as follows (without transfusion, albumin, recombinant human thrombopoietin, or colony-stimulating factors within 14 days prior to randomization):

    Hematologic function

    • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
    • Platelet count ≥ 100 × 10⁹/L
    • Hemoglobin ≥ 90 g/L Hepatic function
    • Total bilirubin ≤ 1.5 × ULN
    • ALT ≤ 2.5 × ULN (≤ 5.0 × ULN in patients with liver metastases)
    • AST ≤ 2.5 × ULN (≤ 5.0 × ULN in patients with liver metastases)
    • Alkaline phosphatase ≤ 2.5 × ULN (≤ 5.0 × ULN in patients with liver and/or bone metastases)
    • Albumin ≥ 25 g/L Renal function
    • Creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula) Coagulation function
    • Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN
    • Prothrombin time (PT) ≤ 1.5 × ULN
    • International normalized ratio (INR) ≤ 1.5 × ULN

12. Female patients must meet one of the following:

    • Postmenopausal (defined as ≥1 year without menstruation not due to other causes), or
    • Surgically sterile (bilateral oophorectomy and/or hysterectomy), or
    • Of childbearing potential and meeting all of the following:
    • Negative serum pregnancy test within 7 days prior to enrollment;
    • Agree to use highly effective contraception (annual failure rate <1%) or remain abstinent from signing the ICF until at least 120 days after the last dose of study drug and 6 months after the last dose of chemotherapy;
    • Not breastfeeding.

13. Male patients must agree to abstain from heterosexual intercourse or use effective contraception during chemotherapy and for at least 6 months after the last dose of chemotherapy, and for at least 120 days after the last dose of study drug, if their partner is of childbearing potential or pregnant.

Exclusion Criteria:

1. History of another active malignancy within the past 5 years or concurrent malignancy, except for cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervix, or breast.

2. Presence of distant metastasis (M1) from gastric cancer.

3. Prior or planned organ or bone marrow transplantation.

4. History of myocardial infarction within 6 months prior to enrollment, or poorly controlled arrhythmia, including QTc prolongation (QTc ≥450 ms in males or ≥470 ms in females, calculated using Fridericia's formula).

5. New York Heart Association (NYHA) class III-IV heart failure, or left ventricular ejection fraction (LVEF) <50% on echocardiography.

6. Known human immunodeficiency virus (HIV) infection.

7. Active pulmonary tuberculosis.

8. Current or prior interstitial lung disease, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary dysfunction that may interfere with the assessment or management of suspected drug-related pulmonary toxicity.

9. Known active or suspected autoimmune disease, except for patients with stable disease not requiring systemic immunosuppressive therapy at enrollment.

10. Receipt of a live vaccine within 28 days prior to enrollment (seasonal influenza vaccines with inactivated virus are allowed).

11. Requirement for systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 14 days prior to enrollment or during the study, except for:

    • Topical or inhaled corticosteroids;
    • Physiologic replacement therapy with prednisone ≤10 mg/day in the absence of active autoimmune disease.

12. Active infection requiring systemic anti-infective therapy within 14 days prior to enrollment (prophylactic antibiotics, such as for urinary tract infection or chronic obstructive pulmonary disease, are allowed).

13. Prior treatment with immune checkpoint inhibitors, including anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies.

14. Participation in another clinical study or receipt of investigational treatment within 14 days prior to initiation of this study.

15. Known severe hypersensitivity to any monoclonal antibody or components of the study drugs.

16. History of substance abuse or illicit drug use; patients who have stopped alcohol consumption may be enrolled.

17. Any condition that, in the investigator's judgment, may increase the risk of study participation or interfere with study treatment, compliance, or evaluation.