Trastuzumab Combined With Retlirafusp Alfa in Treating HER2（Human Epidermal Growth Factor Receptor 2） 2+/3+ Gastric/Gastroesophageal Junction Adenocarcinoma After First-line Systemic Therapy Failure

Prospective, Exploratory Clinical Study of Trastuzumab Combined With Retlirafusp Alfa in Treating HER2 2+/3+ Gastric/Gastroesophageal Junction Adenocarcinoma After First-line Systemic Therapy Failure

Using a prospective, exploratory trial design, we aim to evaluate the efficacy and safety of RC-Trastuzumab combined with Rilafup Alpha in treating first-line systemically treated HER2（Human Epidermal Growth Factor Receptor 2 ） medium-to-high expressing gastric/gastroesophageal junction adenocarcinoma that has failed standard therapy. Participants, after being fully informed and signing the consent form, and passing the screening, enter the treatment phase. The trial medications include RC-Trastuzumab and Rilafup Alpha: RC-Trastuzumab: 4.8 mg/kg i.v.gtt on day 1, every 3 weeks; continue until disease progression, intolerance, or study withdrawal. Rilafup Alpha: 1800 mg or 30 mg/kg i.v.gtt on day 1, every 3 weeks; continue until disease progression, intolerance, or study withdrawal, with a maximum treatment duration of 2 years.

Efficacy assessment: Imaging is done every 2 cycles from the start of therapy until the end of treatment, consent withdrawal, or death. If participants leave the study for any reason and no imaging has been done within 4 weeks before stopping treatment, imaging should be performed at exit. Participants with CR or PR are to have a repeat imaging evaluation 4 weeks later for confirmation. According to RECIST(Response Evaluation Criteria in Solid Tumors version ) 1.1 criteria, for those showing initial PD but clinically stable, confirmation should be done after a 4-week interval, and imaging resumes at the next scheduled time point.

Additionally, the study evaluates drug safety and survival. Safety assessment: Adverse events are graded according to NCI-CTCAE(National Cancer Institute Common Terminology Criteria for Adverse Events) 6.0. During the trial, adverse events should be recorded accurately, including onset, severity, relation to study drugs, duration, actions taken, and outcome. Survival assessment: The follow-up period starts after the last dose of study drug. The study center conducts follow-ups every 3 months during the first year after treatment, then every 6 months, until death or study completion. Follow-ups by phone are acceptable.

Study Overview

• Status: Not yet recruiting
• Conditions: GC; GEJC
• Intervention / Treatment: Drug: Trastuzumab Rezetecan+Retlirafusp alfa

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ying Liu; Phone Number: +8613783604602; Email: zlyyliuying1664@zzu.edu.cn

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Henan Cancer Hospital
      • Contact: Ying Liu Chief Physician; Phone Number: +86 13783604602; Email: zlyyliuying1664@zzu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Fully understand this study and voluntarily sign the informed consent form, with good compliance and cooperation with follow-up;
• Age ≥18 years;
• Eastern Cooperative Oncology Group（ECOG） score 0-1;
• Histologically or cytologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, locally advanced and unresectable, with local recurrence or distant metastasis;
• Immunohistochemistry (IHC) testing for Her2 expression: IHC3+ or IHC2+;
• First-line standard treatment failure in gastric adenocarcinoma or gastroesophageal junction adenocarcinoma: (1) postoperative recurrence or metastasis patients progressing during concurrent chemoradiotherapy; (2) for neoadjuvant/adjuvant therapy containing immunotherapy, if patients progress during treatment or within 6 months after treatment, it is also considered first-line treatment failure;
• Patients must have at least one measurable lesion (according to RECIST 1.1 criteria);
• Major organ functions are normal, meeting the following criteria:(1) Blood routine test standards must meet (no blood transfusion or blood products, and no use of G-CSF or other hematopoietic stimulating factors within 14 days to correct): A. Hemoglobin (Hb) ≥90 g/L; B. Absolute neutrophil count (ANC) ≥1.5 ×10^9/L; C. Platelet count (PLT) ≥80×10^9/L; (2) Biochemical tests must meet the following standards: A. Total bilirubin (TBIL) <1.5 × upper limit of normal (ULN);B. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 ULN, or <5 ULN for patients with liver metastasis; C. Serum creatinine (Cr) ≤1.5 ULN or estimated creatinine clearance >60 ml/min (Cockcroft-Gault formula); D. Urinalysis results: urine protein (UPRO) <2 or 24-hour urine protein <1 g; (3) Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥ lower limit of normal (50%); (4) Coagulation: international normalized ratio (INR) ≤1.5×ULN and activated partial thromboplastin time ≤1.5×ULN;(5) Pulmonary function: forced expiratory volume in 1 second (FEV1) ≥1.2 L, FEV1% ≥70%, carbon monoxide diffusing capacity (DLCO) ≥50%; (6) Cardiac chocardiography: left ventricular ejection fraction (LVEF) ≥50%;(7) Electrocardiogram Fridericia-corrected QT interval (QTcF): women <470 ms, men <450 ms; (8) Others: lipase ≤1.5×ULN (if lipase >1.5×ULN without clinical or imaging evidence of pancreatitis, enrollment is allowed); amylase ≤1.5×ULN (if amylase >1.5×ULN without clinical or imaging evidence of pancreatitis, enrollment is allowed); alkaline phosphatase (ALP) ≤2.5×ULN.
• Women of childbearing potential must agree to use effective contraception during the study and for 6 months after the study; must have a negative serum or urine pregnancy test within 7 days before enrollment, and must not be breastfeeding; men must agree to use contraception during the study and for 6 months after the study.

Exclusion Criteria:

• Known allergy to any investigational drug or its excipients, or allergy to humanized monoclonal antibody products (such as trastuzumab, pertuzumab, etc.).
• (1) Received any investigational drug within 4 weeks before the first use of the study drug; (2) subjects who require systemic treatment with corticosteroids (daily dose >10 mg prednisone equivalent) or other immunosuppressants within 2 weeks before the first use of the study drug, except for using corticosteroids for local esophageal inflammation, allergy prevention, or nausea and vomiting; (3) other special situations need to be discussed with the sponsor. In the absence of active autoimmune disease, inhaled or local steroids and adrenal corticosteroid replacement at doses >10 mg/day prednisone equivalent are allowed; (4) subjects who have received anti-cancer vaccines or live vaccines within 4 weeks before the first administration of the study drug.
• Having any active autoimmune disease or a history of autoimmune disease (such as interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism, hypothyroidism), except for vitiligo or childhood asthma/allergies that have resolved and require no intervention in adulthood; autoimmune-mediated hypothyroidism treated with a stable dose of thyroid replacement hormone and type 1 diabetes patients using a stable dose of insulin can be included.
• History of immunodeficiency, including positive HIV test, or having other acquired or congenital immunodeficiency diseases, or a history of organ transplant or allogeneic bone marrow transplantation.
• Uncontrolled clinical symptoms or diseases of the heart, such as (1) NYHA II or higher heart failure, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias requiring medical intervention.
• Severe infection (CTCAE > Grade 2) within 4 weeks before first use of the study drug, such as severe pneumonia requiring hospitalization, bacteremia, or infections with complications; baseline chest imaging indicating active lung inflammation; symptoms or signs of infection within 2 weeks before first use of the study drug requiring oral or intravenous antibiotics, except for prophylactic antibiotic use; history of interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis, or other uncontrolled acute lung diseases; active pulmonary tuberculosis found by history or CT, or a history of active pulmonary tuberculosis within 1 year before enrollment, or a history of active pulmonary tuberculosis over 1 year ago but not properly treated; subjects with active hepatitis B (HBV DNA ≥2000 IU/mL or 104 copies/mL) or hepatitis C (HCV antibody positive and HCV-RNA above the detection limit of the assay).
• Before using the study drug for the first time, diagnosed with any other malignant tumor is excluded, except for those with low risk of metastasis and death (5-year survival rate >90%), such as fully treated basal cell or squamous cell skin cancer or cervical carcinoma in situ.
• Pregnant or breastfeeding women; subjects of reproductive potential who are unwilling or unable to use effective contraception.
• Patients who, in the investigator's judgment, are considered not suitable to enroll.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab+Retlirafusp alfa	Drug: Trastuzumab Rezetecan+Retlirafusp alfa; Trastuzumab Rezetecan: 4.8 mg/kg i.v.gtt. on day 1, every 3 weeks; use until disease progression, intolerance, or withdrawal from the study. Retlirafusp alfa: 1800 mg or 30 mg/kg i.v.gtt. on day 1, every 3 weeks; use until disease progression, intolerance, or withdrawal from the study, with a maximum treatment duration of 2 years.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective response rate	From the first day of medication to the end of every two cycles.(every two cycles is 42 days)

Secondary Outcome Measures

Outcome Measure	Time Frame
disease control rate	From the first day of medication to the end of every two cycles. (every two cycles is 42 days).
Progression-free survival	From the first day of medication to the end of every two cycles. (every two cycles is 42 days).
Duration of relief	From the first day of medication to the end of every two cycles. (every two cycles is 42 days).
Overall survival	:It is the time from the start of treatment under the study protocol until death from any cause.
AE incidence	From the first day of medication to the end of every cycle. (every cycle is 21 days).

Collaborators and Investigators

• Sponsor: Henan Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 20, 2026
• First Submitted That Met QC Criteria: September 7, 2026
• First Posted (Actual): September 14, 2026

Study Record Updates

• Last Update Posted (Actual): September 14, 2026
• Last Update Submitted That Met QC Criteria: September 7, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: Breakthrough 01

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