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
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 470
- 试验地点
- 1
- 主要终点
- Pathological complete response (pCR) rates
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •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.
研究组 & 干预措施
Chemotherapy
Received placebo combined with investigator's choice of chemotherapy (either SOX or CAPOX regimen
干预措施: SOX or CAPOX regimen (Drug)
Chemotherapy and immunotherapy
Received tislelizumab combined with investigator's choice of chemotherapy (SOX or CAPOX regimen
干预措施: Tislelizumab (Drug)
Chemotherapy and immunotherapy
Received tislelizumab combined with investigator's choice of chemotherapy (SOX or CAPOX regimen
干预措施: SOX or CAPOX regimen (Drug)
结局指标
主要结局
Pathological complete response (pCR) rates
时间窗: Perioperative
To compare the pathological complete response (pCR) rates between tislelizumab plus chemotherapy and placebo plus chemotherapy as perioperative therapy for MHC-II-positive locally advanced gastric or gastroesophageal junction adenocarcinoma .
次要结局
未报告次要终点
研究者
Xiangdong Cheng
Principal Investigator
Zhejiang Cancer Hospital