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

NCT07802288 | Not Yet Recruiting Phase 2

• 1 other identifier: E20260976
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Gastric Adenocarcinoma and Gastroesophageal Junction Adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• 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

Study Arms (2)

Cohort 1: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX Perioperative Therapy + Retlirafusp Alfa

EXPERIMENTAL

Drug: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX

Cohort 2: Trastuzumab Rezetecan + Retlirafusp Alfa (Without Chemotherapy) Perioperative Therapy + Re

EXPERIMENTAL

Drug: Trastuzumab Rezetecan + Retlirafusp Alfa

Interventions

Trastuzumab Rezetecan + Retlirafusp Alfa DRUG

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

Cohort 2: Trastuzumab Rezetecan + Retlirafusp Alfa (Without Chemotherapy) Perioperative Therapy + Re

Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX DRUG

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

Cohort 1: Trastuzumab Rezetecan + Retlirafusp alfa + CAPOX Perioperative Therapy + Retlirafusp Alfa

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Tianjin Medical University Cancer Institute and Hospital: lead

Study Sites (1)

Tianjin Medical University Cancer Institute & Hospital

Tianjin, Tianjin Municipality, 300000, China

Location

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2026
• First Posted: September 3, 2026
• Study Start: September 30, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): September 30, 2031
• Last Updated: September 3, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)