Feasibility of Circulating Tumor DNA Based Minimal Residual Disease-Guided Adjuvant Therapy in Locally Advanced Gastric Cancer With Neoadjuvant Treatment: An Open-Label, Randomized, Multi-Centered Phase III Trial

Plain English Summary

Feasibility of Circulating Tumor DNA Based Minimal Residual Disease-Guided Adjuvant Therapy in Locally Advanced Gastric Cancer With Neoadjuvant Treatment is a Phase 3 clinical trial sponsored by Shanghai Zhongshan Hospital studying Gastric / Gastroesophageal Junction Adenocarcinoma. Tests if circulating tumor DNA (ctDNA) can guide whether adjuvant therapy is needed after surgery for locally advanced gastric cancer. For patients who have had neoadjuvant therapy and are scheduled for surgery, this trial will use ctDNA to determine if adjuvant therapy is necessary. Participation involves undergoing neoadjuvant therapy, surgery, and ctDNA testing to guide post-surgery treatment. Alternative treatments include standard adjuvant therapy as recommended by clinical guidelines. The trial aims to enroll 304 participants.

Official Summary

For locally advanced gastric adenocarcinoma/esophagogastric junction adenocarcinoma, the currently recommended treatment strategy per clinical guidelines is radical gastrectomy combined with perioperative therapy (including chemotherapy, immunotherapy, etc.). This approach involves several cycles of neoadjuvant therapy prior to surgery, followed by the surgical procedure, and then several cycles of adjuvant therapy post-surgery. This regimen is generally considered to offer favorable efficacy, ultimately leading to improved survival outcomes for patients. However, some patients are unable to complete the prescribed postoperative adjuvant therapy due to factors such as poor physical condition after surgery or cumulative treatment toxicity. Findings from the retrospective SPACE-FLOT study preliminarily suggest that for patients with a favorable response to neoadjuvant therapy, postoperative adjuvant therapy may not confer additional survival benefit, while potentially increasing the risk of treatment-related adverse events. Therefore, the investigators aim to utilize the latest technological approaches to identify patients who could safely forgo adjuvant therapy, enabling personalized treatment decisions, reducing unnecessary treatment, and thereby maximizing patients' long-term survival benefits. To achieve this objective, the investigators have identified circulating tumor DNA (ctDNA) testing as a potential solution. ctDNA refers to DNA fragments released by tumor cells into the extracellular space (e.g., into the bloodstream). By drawing a small amount of peripheral blood and analyzing the ctDNA within, it is possible to detect minimal residual disease (MRD) that is difficult to identify through conventional imaging methods (such as CT or MRI) after treatment. MRD is considered a critical factor that may lead to tumor recurrence. Utilizing ctDNA to detect MRD enables a convenient and accurate assessment of tumor status and treatment efficacy, thereby offering the

Who Can Participate

Here is what you need to know about eligibility for this trial. Ages 18 and older, confirmed gastric or gastroesophageal junction adenocarcinoma, fit for surgery, and able to provide informed consent. Excludes those with significant health issues, prior malignancies, or those unsuitable for study. Must be able to provide tumor tissue for genetic analysis and meet specific blood test criteria. Females of childbearing potential must be using contraception and have a negative pregnancy test. This trial is studying Gastric / Gastroesophageal Junction Adenocarcinoma, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the time until disease recurrence or death, which is crucial for understanding the effectiveness of ctDNA-guided therapy in improving patient survival. The specific primary outcome measures are: Disease-Free Survival (DFS) (The time from radical gastrectomy to documented disease recurrence or death, whichever occurs first, assessed up to 3 years.). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to personalize treatment for gastric cancer by using ctDNA to identify patients who can safely skip adjuvant therapy, potentially reducing side effects and improving long-term survival As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Gastric / Gastroesophageal Junction Adenocarcinoma, where improved treatment options are needed.

Investor Insight

The market for personalized cancer treatments is growing, and this trial could fill a significant treatment gap by offering a more tailored approach to adjuvant therapy. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential benefits of ctDNA testing. Participation involves neoadjuvant therapy, surgery, and ctDNA testing to guide post-surgery treatment. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 304 participants

Interventions

• DRUG: Standard neoadjuvant therapy: Chemotherapy/Targeted Therapy/Immunotherapy — Participants will receive 4 cycles of neoadjuvant therapy based on CSCO/NCCN guidelines. The specific regimen is determined by molecular characteristics and clinical practice: 1. Chemotherapy: Options include SOX, DOS, FLOT, XELOX (CapeOx), or FOLFOX. 2. HER2-Positive: Trastuzumab combined with chemotherapy, with or without immunotherapy. 3. Immunotherapy: PD-(L)1 inhibitors may be administered as monotherapy or in combination with chemotherapy. Dosages and administration follow standard pharmac
• PROCEDURE: Radical gastrectomy — Radical gastrectomy with standard D2 lymphadenectomy will be performed.
• DRUG: Standard adjuvant therapy: Chemotherapy/Targeted Therapy/Immunotherapy — For control arm, postoperative adjuvant therapy begins 4-6 weeks post-surgery and consists of 4 cycles. The regimen generally mirrors the neoadjuvant therapy received. Dosages and administration follow standard pharmaceutical labeling and institutional protocols. Patients deemed unsuitable for adjuvant therapy by experienced clinicians will undergo observation.
• DRUG: ctDNA-MRD-guided adjuvant therapy — Participants in the Experimental Arm will initially receive 4 cycles of neoadjuvant therapy followed by D2 radical gastrectomy. Postoperative management is strictly guided by ctDNA MRD status assessed at 4 weeks post-surgery: 1. ctDNA MRD-Negative Subgroup: Participants will not receive adjuvant therapy and will undergo active surveillance (observation). 2. ctDNA MRD-Positive Subgroup: Participants will receive 4 cycles of adjuvant therapy, initiating 4-6 weeks after surgery. The regimen general

Primary Outcomes

• Disease-Free Survival (DFS) (The time from radical gastrectomy to documented disease recurrence or death, whichever occurs first, assessed up to 3 years.)

Secondary Outcomes

• Quality of Life (QoL)-EORTC QLQ-C30 (From screening (within 21 days before randomization) to 15 months after surgery.)
• Quality of Life (QoL)-QLQ-STO-22 (From screening (within 21 days before randomization) to 15 months after surgery.)
• Overall Survival (OS) (The time from radical gastrctomy to death from any cause, assessed up to 3 years.)
• Proportion of Adjuvant Therapy Implementation (From the date of radical surgery to the initiation of adjuvant therapy (or up to 16 weeks after surgery if no therapy is given).)
• Changes in ctDNA Levels During Treatment (From randomization to 5 months post surgery.)

Full Eligibility Criteria

Inclusion Criteria:

1. Able to provide written informed consent (ICF) and capable of understanding and agreeing to comply with the study requirements and assessment schedule;
2. Male or female aged ≥ 18 years;
3. Histologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, with clinical TNM stage (according to the 8th edition of the AJCC/UICC clinical TNM staging system for gastric cancer; see Appendix 1) of cIIB-IVA, and the primary gastric tumor assessed as amenable to radical resection;
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix 2), fit to undergo surgical treatment with no contraindications to surgery;
5. Capable of providing adequate tumor tissue obtained via gastroscopy (or other means) prior to neoadjuvant treatment for whole-exome sequencing;
6. Females of childbearing potential must have a negative pregnancy test within 7 days before initiation of neoadjuvant treatment. Males and females of childbearing potential must agree to use adequate contraception during the study period and for 24 months after the last dose of study treatment (see Appendix 3);
7. Hematologic and biochemical parameters meeting the following criteria prior to neoadjuvant treatment:

   * Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
   * Platelet count (PLT) ≥ 75 × 10⁹/L
   * Hemoglobin (Hb) ≥ 80 g/L
   * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)
   * Serum creatinine (Cr) ≤ 1.5 × ULN or estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m²
   * Serum albumin (ALB) ≥ 30 g/L
   * For subjects not receiving anticoagulant therapy: international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; for subjects receiving anticoagulant therapy: PT within the expected therapeutic range for the anticoagulant;
8. No prior anticancer therapy for the current study-related tumor prior to initiation of neoadjuvant treatment.

Exclusion Criteria:

1. Patients deemed by the investigator to have significant contraindications to or intolerance of neoadjuvant/adjuvant therapy;
2. Female patients of childbearing potential who have not undergone surgical sterilization or are not using adequate contraceptive measures, pregnant or lactating women, or male patients planning to father a child within a short period;
3. Any severe or uncontrolled systemic disease, including but not limited to uncontrolled hypertension, active hemorrhage, diabetes mellitus, etc.;
4. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis, human immunodeficiency virus (HIV) infection, etc.;
5. Prior history of malignancy or current presence of another malignancy, except for completely resected basal cell or squamous cell skin cancer, superficial bladder cancer, or in situ carcinoma of the prostate, cervix, or breast with at least 5 years without recurrence;
6. Other conditions deemed by the investigator to render the patient unsuitable for study participation.

Trial Locations

• Zhongshan Hospital, Fudan University, Shanghai, Shanghai Municipality, China

Frequently Asked Questions

Related Conditions

• Gastric cancer, gastroesophageal junction adenocarcinoma, and other gastrointestinal malignancies.

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