Perioperative Tislelizumab Plus Chemotherapy Versus Chemotherapy Alone in MHC-II-Positive Gastric/GEJ Cancer

Official title

A Multicenter, Randomized, Double-blind, Phase III Clinical Trial of Tislelizumab Combined With Chemotherapy Versus Placebo Plus Chemotherapy as Perioperative Treatment for MHC Class II-positive Locally Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Overview

Investigators has conducted a series of studies on patient selection for perioperative immunotherapy in locally advanced gastric cancer. Results from prospective single-arm trial (NCT05739045) demonstrated that 21.74% of patients achieved pathological complete response (pCR) after receiving neoadjuvant nivolumab combined with SOX regimen. Notably, investigators identified that the sensitive group exhibited upregulated MHC-II expression in malignant cells at baseline, with enriched pathways including interferon-gamma signaling and MHC class II antigen presentation. The pCR rate was significantly higher in MHC-II positive patients compared to MHC-II negative patients (36.84% vs 11.11%, P=0.038). Subsequent retrospective analyses and another prospective single-arm study focusing on MHC-II positive populations consistently showed superior short-term treatment outcomes with immunotherapy plus chemotherapy in this subgroup. Building upon these preliminary findings from small-scale studies and considering current developments in the field, we are now initiating this multicenter, randomized, double-blind, placebo-controlled phase III clinical trial. The study aims to evaluate the efficacy and safety of tislelizumab combined with chemotherapy versus placebo plus chemotherapy as perioperative treatment for MHC-II positive patients with locally advanced gastric or gastroesophageal junction adenocarcinoma.

Interventions

• Drug Tislelizumab
  Received tislelizumab combined with investigator's choice of chemotherapy
• Drug SOX or CAPOX regimen
  chemotherapy (SOX or CAPOX regimen)

Primary outcome measures

• Pathological complete response (pCR) rates [Time frame: Perioperative]

Eligibility criteria

Inclusion criteria

• Willingness to participate and signed informed consent form
• ≥18 years old
• Histologically confirmed gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma
• MHC-II immunohistochemistry (IHC) 2+/3+
• Locally advanced disease (cT3-4a, N+, M0) confirmed by CT and/or diagnostic laparoscopy (AJCC 8th edition)
• No previous anticancer therapy (surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.)
• Scheduled to undergo curative resection after neoadjuvant therapy
• Ability to swallow oral medication
• ECOG performance status 0-1
• Estimated survival ≥6 months
• Hematological (without transfusion/G-CSF support within 14 days):ANC ≥1.5×10⁹/, Platelets ≥80×10⁹/L, Hemoglobin ≥80 g/L. Hepatic/Renal: Total bilirubin <1.5×ULN, ALT/AST ≤2.5×ULN, Serum creatinine ≤1.5×ULN or CrCl >50 mL/min (calculated by Cockcroft-Gault formula: Male: CrCl = \[(140-age) × weight (kg)\] / (72 × serum Cr \[mg/dL\]), Female: CrCl = \[(140-age) × weight (kg)\] / (72 × serum Cr \[mg/dL\]) × 0.85.
• Contraception Requirements: Female participants of childbearing potential: Negative serum pregnancy test within 7 days before enrollment; agreement to use highly effective contraception during treatment and for 120 days after last dose. Female participants of childbearing potential: Negative serum pregnancy test within 7 days before enrollment; agreement to use highly effective contraception during treatment and for 120 days after last dose.

Exclusion criteria

• Tumors deemed unresectable due to disease extent, surgical contraindications, or patient refusal.
• Known microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors.
• History of or concurrent other malignancies (except adequately treated non-melanoma skin cancer or carcinoma in situ).
• Chronic or clinically significant conditions that may compromise treatment tolerance (e.g., severe cardiac disease, uncontrolled hypertension, significant hepatic/renal dysfunction).
• History of gastrointestinal perforation, intra-abdominal abscess, or bowel obstruction within 3 months (or clinical/radiologic suspicion of obstruction).
• Presence of active ulcers, non-healing wounds, or fractures.
• Arterial/venous thrombosis within 6 months (e.g., stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism).
• Urinalysis showing ≥++ protein with confirmed 24-hour urine protein >1.0 g.
• Requiring systemic antibiotics, antivirals, or antifungals.
• Hepatitis B: HBsAg-positive with HBV DNA ≥500 IU/mL. Hepatitis C: HCV antibody-positive with HCV RNA above ULN.
• Congenital or acquired (e.g., HIV infection).
• Active autoimmune disease or history of autoimmune disease with relapse potential.
• Prior or planned organ/allogeneic bone marrow transplantation.
• Interstitial lung disease (ILD), history of steroid-treated ILD, active pneumonia on screening CT, or active tuberculosis.
• Current or recent use of immunosuppressants or systemic corticosteroids (except physiologic replacement doses).
• Received live attenuated vaccines within 28 days before treatment or requiring them during/within 60 days post-treatment.
• Known allergy to any study drug or excipients.
• Currently breastfeeding.
• Any condition that, per investigator judgment, may jeopardize patient safety or study completion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

China · 1 center

• Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital — Hangzhou

Identifiers

NCT: NCT07068516 · Mountain-04

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗