A Multicenter, Randomized Phase II Study of Trastuzumab Rezetecan Combined With Retlirafusp Alfa With or Without CAPOX Regimen for Perioperative Treatment of Resectable Locally Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Pathological Complete Response (pCR)
研究概览
简要总结
This two-stage, multicenter, randomized open-label phase II trial enrolls untreated resectable stage II-III gastric/gastroesophageal junction adenocarcinoma patients with any HER2 expression. Stage 1 is a safety lead-in cohort of 6 patients receiving Trastuzumab Rezetecan(SHR-A1811)+Retlirafusp alfa(SHR-1701) plus CAPOX to assess dose-limiting toxicity (DLT) within 21 days after initial dosing. If safety risk is acceptable, stage 2 will randomize 74 eligible patients 1:1 into two parallel cohorts stratified by HER2 status. Cohort1 receives perioperative Trastuzumab Rezetecan(SHR-A1811)+Retlirafusp alfa(SHR-1701)+CAPOX; Cohort2 receives dual targeted-immunotherapy without chemotherapy (Trastuzumab Rezetecan+Retlirafusp alfa). All patients undergo D2 radical gastrectomy after neoadjuvant therapy, followed by adjuvant treatment and Retlirafusp alfa(SHR-1701) maintenance up to maximum 17 total cycles. The primary endpoint is pCR rate evaluated by CAP pathological criteria. Secondary endpoints include R0 resection rate, EFS, DFS, OS and perioperative/surgical/systemic safety profiles. Biomarker exploratory analysis will be performed to evaluate the correlation between PD-L1, MSI, TMB and clinical efficacy.
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
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntarily sign written informed consent before any study-related procedures
- •Age ≥18 and ≤75 years old
- •Histopathologically confirmed gastric or gastroesophageal junction adenocarcinoma
- •AJCC 8th edition stage II-III resectable disease (cT1-2N+M0, T3-4aNanyM0); negative peritoneal cytology (CY0) confirmed by pre-study laparoscopy
- •HER2 expression status: High HER2 (IHC 3+ or IHC 2+ FISH-positive) OR Low/Intermediate HER2 (IHC 2+ FISH-negative / IHC 1+)
- •No prior systemic anti-tumor therapy (chemotherapy, targeted therapy, immunotherapy, radiotherapy, radical gastrectomy)
- •Planned radical D2 gastrectomy after neoadjuvant treatment completion
- •Able to swallow oral capecitabine tablets intact
- •ECOG Performance Status 0 or 1
- •Estimated overall survival ≥12 months
- •Adequate organ function (no blood products/G-CSF within prior 14 days):
- •ANC ≥1.5×10⁹/L; PLT ≥80×10⁹/L; Hb ≥90 g/L
- •Total bilirubin <1.5×ULN; ALT/AST ≤2.5×ULN
- •Serum Cr ≤1.5×ULN or CrCl >50 mL/min
- •INR, PT, APTT ≤1.5×ULN
- •Fertile female subjects: Negative serum pregnancy test within 72 hours before first dose; all fertile participants agree to effective contraception during treatment and required post-treatment contraceptive window
排除标准
- •Siewert type I GEJ tumor or Siewert II tumor requiring cervicothoracic surgical approach
- •Confirmed peritoneal metastasis, positive peritoneal cytology (CY1), or AJCC T4b disease
- •Tumor unresectable or absolute contraindication to radical gastrectomy
- •History of other malignant tumor within past 5 years (excluding cured basal cell skin carcinoma, cervical/breast carcinoma in situ)
- •Uncontrolled hypertension (SBP≥160 mmHg or DBP≥100 mmHg despite optimal medical management)
- •Cardiac dysfunction: NYHA grade ≥2 heart failure, LVEF <50%, unstable angina, myocardial infarction within 1 year, prolonged QTc interval (male >450ms, female >470ms), family history of sudden cardiac death <40 years old
- •GI perforation/fistula within 6 months, intestinal obstruction within 3 months (not fully resolved)
- •Active severe bleeding disorder or active peptic ulcer disease
- •Arterial/venous thromboembolic event within past 6 months (stroke, DVT, pulmonary embolism etc.)
- •Severe uncontrolled infection (≥CTCAE grade 2) within 4 weeks prior to first dose
- •Active viral hepatitis (HBV DNA ≥2000 IU/mL; active HCV viremia) or HIV positive
- •History or active interstitial lung disease, pulmonary fibrosis, active tuberculosis
- •Active autoimmune disease requiring long-term systemic immunosuppressive therapy
- •Systemic corticosteroid dose >10 mg prednisone equivalent within 7 days pre-treatment
- •Received live attenuated vaccine within 28 days before enrollment
- •Hypersensitivity to any study drug or excipients
- •Participation in other interventional clinical trials within 4 weeks prior to first dose
- •Lactating female subjects
- •Any medical, psychiatric or social condition judged by investigator to interfere with study compliance or subject safety
研究组 & 干预措施
Cohort 1: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX Perioperative Therapy + Retlirafusp Alfa
干预措施: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX (Drug)
Cohort 2: Trastuzumab Rezetecan + Retlirafusp Alfa (Without Chemotherapy) Perioperative Therapy + Re
干预措施: Trastuzumab Rezetecan + Retlirafusp Alfa (Drug)
结局指标
主要结局
Pathological Complete Response (pCR)
时间窗: after surgery，within approximately 4-6 weeks
Proportion of subjects achieving CAP Tumor Regression Grade 0 (TRG0), defined as no viable malignant cells detected in primary gastric tumor and all regional lymph nodes after radical D2 gastrectomy
次要结局
- R0 Resection Rate(within approximately 2 weeks after surgery)
- Event-Free Survival (EFS)(Up to 5 years)
- Overall Survival (OS)(Up to 5 years)
- Incidence, severity and causality of TEAEs, SAEs graded by NCI-CTCAE 6.0.(From first study drug to 90 days after last drug administration)