Phase II Study of Trastuzumab Rezetecan Combined With Retlirafusp Alfa With or Without CAPOX as Perioperative Therapy for Resectable Locally Advanced Gastric/Gastroesophageal Junction Adenocarcinoma

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric Adenocarcinoma and Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX; Drug: Trastuzumab Rezetecan + Retlirafusp Alfa

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300000
      • Tianjin Medical University Cancer Institute & Hospital
      • Contact: Liangliang Wu; Phone Number: 13752273612; Email: wuliangliang830996@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX Perioperative Therapy + Retlirafusp Alfa	Drug: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX; 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; Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles; Drug: Oxaliplatin Description: 60 mg/m² IV Q3W, only 3 neoadjuvant cycles; Drug: Capecitabine Description: 750 mg/m² oral twice daily, 2 weeks on / 1 week off; 3 neoadjuvant + 3 adjuvant cycles; Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose
Experimental: Cohort 2: Trastuzumab Rezetecan + Retlirafusp Alfa (Without Chemotherapy) Perioperative Therapy + Re	Drug: Trastuzumab Rezetecan + Retlirafusp Alfa; 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; Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles; Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR)	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	after surgery，within approximately 4-6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 Resection Rate	The proportion of subjects who achieve R0 resection confirmed by postoperative surgical pathology.	within approximately 2 weeks after surgery
Event-Free Survival (EFS)	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)	Up to 5 years
Overall Survival (OS)	Overall survival is length of time from randomization until the date of death due to any cause.	Up to 5 years
Incidence, severity and causality of TEAEs, SAEs graded by NCI-CTCAE 6.0.	Assessment of safety	From first study drug to 90 days after last drug administration

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): September 30, 2031

Study Registration Dates

• First Submitted: August 19, 2026
• First Submitted That Met QC Criteria: September 2, 2026
• First Posted (Actual): September 3, 2026

Study Record Updates

• Last Update Posted (Actual): September 3, 2026
• Last Update Submitted That Met QC Criteria: September 2, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: E20260976

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No