The purpose of this study is to investigate the safety and efficacy of conversion therapy using HFRT combined with ICT in locally advanced or metastatic unresectable GEJA.
Histologically and/or cytologically confirmed diagnosis of locally advanced gastroesophageal junction adenocarcinoma (GEJA), Siewert type I-III, with staging of cT3-4, any N, M0 or cT2 N+, M0, according to the AJCC 8th edition.
Resectable locally advanced disease as determined by multidisciplinary team (MDT) assessment.
Age ≥18 years, regardless of sex.
ECOG performance status of 0 or 1.
Diagnosed as mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) by immunohistochemistry or gene testing.
Evidence of peritoneal or multi-organ metastatic disease, as confirmed by chest and abdominal CT, bone scan, or MRI (in cases with suspected osseous lesions).
History of or concurrent other malignancies within the past 5 years, excluding cured basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
Known allergy to any component of the investigational drugs, history of severe hypersensitivity, or any contraindication to study drugs.
Parallel
hypofractionated radiotherapy
RadiationIn Phase Ib, HFRT will be administered at one of three dose levels: 3 Gy × 5 fractions, 4 Gy × 5 fractions, or 5 Gy × 5 fractions. The recommended dose determined in Phase Ib will be used in Phase II (delivered as 5 fractions).
SOX Chemotherapy
DrugSOX chemotherapy regimen: Oxaliplatin 130 mg/m² administered by intravenous infusion on Day 1; S-1 administered orally for 14 consecutive days followed by a 7-day rest period. The dosage of S-1 is based on body surface area (BSA): 40 mg twice daily for BSA ≤1.5 m², 50 mg twice daily for BSA between 1.5-1.6 m², and 60 mg twice daily for BSA ≥1.6 m². Each cycle is repeated every 3 weeks.
PD-1 inhibitor
DrugSintilimab 200 mg administered by intravenous infusion on Day 1 of each 3-week cycle.
Safety and tolerability in Phase Ib
Safety will be assessed based on clinical adverse events, vital signs, and abnormalities in laboratory tests during the study period. Adverse events (AEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. All deaths occurring within 90 days after the first dose of treatment or within 30 days after the last dose will be listed along with the causes of death. Laboratory abnormalities will be categorized according to NCI-CTCAE version 5.0. Maximum Tolerated Dose (MTD): If ≥1 out of 3 patients in a given dose cohort experiences radiotherapy-related dose-limiting toxicity (DLT) within 90 days, that dose level will be considered intolerable. The next lower dose level will be defined as the MTD. The MTD cohort must include at least 6 evaluable patients.
ORR rate in Phase II
Objective Response Rate (ORR):ORR is defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) as determined by investigators based on RECIST version 1.1. The initial CR or PR must be confirmed by repeat imaging at least 4 weeks after the first documentation of response.
R0 resection rate
number of R0 surgery divide all participants
DOR (Duration of Response)
Duration from the first documented complete response (CR) or partial response (PR) to the date of disease progression (PD) or death from any cause.
PFS (Progression-Free Survival)
Time from the first administration of the study treatment to disease progression (PD) or death from any cause, whichever occurs first.
OS (Overall Survival)
Time from the initiation of study treatment to death from any cause.
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