Mannatide Combined With CAPOX and Tislelizumab for Advanced Gastric Cancer.

A Multicenter, Single-Arm, Phase II Study of Mannatide Combined With CAPOX and Tislelizumab as First-Line Treatment for Recurrent or Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma.

This is a multicenter, open-label, single-arm phase II study evaluating the efficacy and safety of mannatide in combination with CAPOX chemotherapy and tislelizumab as first-line treatment for patients with recurrent or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

Eligible patients will receive oxaliplatin, capecitabine, tislelizumab, and oral mannatide. Tumor response will be assessed according to RECIST version 1.1. Patients without disease progression after induction treatment may continue maintenance therapy with capecitabine, tislelizumab, and mannatide.

The primary objective is to evaluate objective response rate (ORR). Secondary objectives include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and safety. Exploratory analyses will investigate immune microenvironment changes and potential predictive biomarkers using blood, tumor tissue, and stool samples.

Gastric cancer remains one of the leading causes of cancer-related mortality worldwide. Although immune checkpoint inhibitors combined with chemotherapy have improved outcomes in advanced gastric and gastroesophageal junction adenocarcinoma, many patients still fail to achieve durable responses.

Mannatide is an immunomodulatory agent that has been shown to enhance both innate and adaptive immune responses. Preclinical and clinical studies suggest that mannatide may improve antitumor immunity through activation of macrophages, enhancement of antigen presentation, stimulation of T-cell proliferation, and promotion of natural killer cell activity. These properties provide a rationale for combining mannatide with chemotherapy and immune checkpoint blockade.

This study is a multicenter, open-label, single-arm phase II trial enrolling approximately 52 patients with unresectable recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. Participants will receive CAPOX chemotherapy (oxaliplatin plus capecitabine), tislelizumab, and oral mannatide as first-line treatment.

Treatment will be administered for six induction cycles. Tumor assessments will be performed every two cycles according to RECIST version 1.1. Patients without disease progression may continue maintenance therapy consisting of capecitabine, tislelizumab, and mannatide until disease progression, unacceptable toxicity, withdrawal of consent, initiation of another anticancer therapy, death, or completion of the maximum treatment duration.

The primary endpoint is objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and safety. Exploratory endpoints include single-cell RNA sequencing, single-cell T-cell receptor sequencing, multiplex immunofluorescence analysis, and gut microbiome profiling to identify biomarkers associated with treatment response.

Inclusion Criteria:

1. Histologically or cytologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, including signet ring cell carcinoma, mucinous adenocarcinoma, and hepatoid adenocarcinoma.
2. Unresectable recurrent or metastatic disease confirmed by imaging and surgical evaluation.
3. Age 18 to 75 years.
4. Expected survival greater than 3 months.
5. No prior systemic therapy for recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. Previous neoadjuvant or adjuvant therapy is allowed if completed at least 6 months before enrollment without evidence of recurrence or progression.
6. ECOG performance status 0-1.
7. At least one measurable lesion according to RECIST version 1.1.
8. Availability of tumor tissue for PD-L1 testing.
9. Adequate hematologic, hepatic, renal, and coagulation function.
10. Recovery of prior treatment-related toxicities to Grade 0-1 or baseline level.
11. Negative pregnancy test for women of childbearing potential and agreement to use effective contraception.
12. Ability to understand and willingness to sign informed consent.

Exclusion Criteria:

1. HER2-positive gastric or gastroesophageal junction adenocarcinoma.
2. Squamous cell carcinoma, undifferentiated carcinoma, or mixed histology.
3. Active or uncontrolled central nervous system metastases.
4. Uncontrolled pleural effusion, ascites, or clinically significant pericardial effusion.
5. Weight loss greater than 20% within 2 months before enrollment.
6. Major surgery within 28 days before enrollment.
7. Prior anti-PD-1, anti-PD-L1, anti-CTLA-4, or other immune checkpoint inhibitor therapy.
8. Active autoimmune disease requiring systemic treatment.
9. Active hepatitis B, hepatitis C, or HIV infection.
10. Interstitial lung disease or uncontrolled systemic disease.
11. Significant cardiovascular disease within 6 months before enrollment.
12. Known hypersensitivity to study drugs or their components.
13. Participation in another interventional clinical trial within 4 weeks before enrollment.
14. History of substance abuse or severe psychiatric disorder.
15. History of rheumatic heart disease or known hypersensitivity to mannatide.
16. Any condition that, in the opinion of the investigator, would make participation unsafe or interfere with study evaluation.