Gastric Adenocarcinoma and Gastroesophageal Junction Adenocarcinoma
Conditions
Brief summary
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.
Interventions
DRUGTrastuzumab Rezetecan + Retlirafusp alfa + CAPOX
1. Drug: Trastuzumab Rezetecan Description: IV infusion Q3W; Cycle 1 loading dose 6.4 mg/kg, subsequent cycles 4.8 mg/kg; administered for 3 neoadjuvant cycles and 3 adjuvant cycles 2. Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles 3. Drug: Oxaliplatin Description: 60 mg/m² IV Q3W, only 3 neoadjuvant cycles 4. Drug: Capecitabine Description: 750 mg/m² oral twice daily, 2 weeks on / 1 week off; 3 neoadjuvant + 3 adjuvant cycles 5. Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose
DRUGTrastuzumab Rezetecan + Retlirafusp Alfa
1. Drug: Trastuzumab Rezetecan Description: IV infusion Q3W; Cycle 1 loading dose 6.4 mg/kg, subsequent cycles 4.8 mg/kg; administered for 3 neoadjuvant cycles and 3 adjuvant cycles 2. Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles 3. Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose
Sponsors
Tianjin Medical University Cancer Institute and Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntarily sign written informed consent before any study-related procedures 2. Age ≥18 and ≤75 years old 3. Histopathologically confirmed gastric or gastroesophageal junction adenocarcinoma 4. AJCC 8th edition stage II-III resectable disease (cT1-2N+M0, T3-4aNanyM0); negative peritoneal cytology (CY0) confirmed by pre-study laparoscopy 5. HER2 expression status: High HER2 (IHC 3+ or IHC 2+ FISH-positive) OR Low/Intermediate HER2 (IHC 2+ FISH-negative / IHC 1+) 6. No prior systemic anti-tumor therapy (chemotherapy, targeted therapy, immunotherapy, radiotherapy, radical gastrectomy) 7. Planned radical D2 gastrectomy after neoadjuvant treatment completion 8. Able to swallow oral capecitabine tablets intact 9. ECOG Performance Status 0 or 1 10. Estimated overall survival ≥12 months 11. 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 12. 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
Exclusion criteria
1. Siewert type I GEJ tumor or Siewert II tumor requiring cervicothoracic surgical approach 2. Confirmed peritoneal metastasis, positive peritoneal cytology (CY1), or AJCC T4b disease 3. Tumor unresectable or absolute contraindication to radical gastrectomy 4. History of other malignant tumor within past 5 years (excluding cured basal cell skin carcinoma, cervical/breast carcinoma in situ) 5. Uncontrolled hypertension (SBP≥160 mmHg or DBP≥100 mmHg despite optimal medical management) 6. 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 7. GI perforation/fistula within 6 months, intestinal obstruction within 3 months (not fully resolved) 8. Active severe bleeding disorder or active peptic ulcer disease 9. Arterial/venous thromboembolic event within past 6 months (stroke, DVT, pulmonary embolism etc.) 10. Severe uncontrolled infection (≥CTCAE grade 2) within 4 weeks prior to first dose 11. Active viral hepatitis (HBV DNA ≥2000 IU/mL; active HCV viremia) or HIV positive 12. History or active interstitial lung disease, pulmonary fibrosis, active tuberculosis 13. Active autoimmune disease requiring long-term systemic immunosuppressive therapy 14. Systemic corticosteroid dose \>10 mg prednisone equivalent within 7 days pre-treatment 15. Received live attenuated vaccine within 28 days before enrollment 16. Hypersensitivity to any study drug or excipients 17. Participation in other interventional clinical trials within 4 weeks prior to first dose 18. Lactating female subjects 19. Any medical, psychiatric or social condition judged by investigator to interfere with study compliance or subject safety
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| R0 Resection Rate | within approximately 2 weeks after surgery | The proportion of subjects who achieve R0 resection confirmed by postoperative surgical pathology. |
| Event-Free Survival (EFS) | Up to 5 years | EFS is the time from date of randomization until the date of disease progression or death.(assessed by the investigator per RECIST v1.1 criteria) |
| Overall Survival (OS) | Up to 5 years | Overall survival is length of time from randomization until the date of death due to any cause. |
| Incidence, severity and causality of TEAEs, SAEs graded by NCI-CTCAE 6.0. | From first study drug to 90 days after last drug administration | Assessment of safety |
Countries
China
Outcome results
None listed