A Prospective, Open-label, Randomized, Controlled Phase II Clinical Trial Exploring the Efficacy and Safety of Thymosin Alpha 1 Combined With PD-1 Monoclonal Antibody and Neoadjuvant Chemoradiotherapy for cStage III Gastroesophageal Junction Adenocarcinoma
This is a prospective, single-center, randomized controlled, phase II clinical trial. The study aims to enroll 48 patients with resectable, locally advanced gastroesophageal junction adenocarcinoma who have not received any treatment. After obtaining informed consent and meeting the inclusion/exclusion criteria, patients were randomly assigned preoperatively in a 1:2 ratio: Arm A. Radiochemoimmunotherapy group (n=16): 3 cycles of serplulimab combined with modified SOX (mSOX) combined with radiotherapy, as details: Cycle 1: Serplulimab: 300 mg, i.v., D1 Oxaliplatin: 130 mg/m², i.v., D1 S-1 (Tegafur/Gimeracil/Oteracil): Oral administration: 40 mg twice daily for BSA \< 1.25 m²; 50 mg twice daily for BSA 1.25 to \<1.5 m²; 60 mg twice daily for BSA ≥ 1.5 m². Administered from D1 to D14, followed by a rest period from D15 to D21. This cycle lasts 21 days. Cycle 2: Serplulimab: 300 mg, i.v., D1 S-1: Oral administration: 40 mg twice daily from D1 to D14 of the treatment cycle. Radiotherapy: Commences between D2 and D5 after the start of Cycle 2. The clinical target volume (CTV) is defined as the endoscopically marked tumor boundary and adjacent metastatic lymph nodes plus a 5-10 mm margin. The planning target volume (PTV) is generated by adding an additional 5-10 mm margin to the CTV. The planned dose to the PTV is 44 Gy administered in 22 fractions, with 5 fractions per week. This is followed by a 7-day rest interval. This cycle lasts 33 days. Cycle 3: Serplulimab: 300 mg, i.v., D1 Oxaliplatin: 130 mg/m², i.v., D1 Fluorouracil Injection: Administered as a 400 mg/m² intravenous bolus on day 1, followed immediately by a continuous intravenous infusion of 2400-3000 mg/m² over 46 hours. This is followed by a 7-day rest period. This cycle lasts 9 days. Arm B: Immunomodulation group (n=32): 3 cycles of serplulimab combined with mSOX combined with radiotherapy (as described above) and 9 weeks of neoadjuvant thymosin; After neoadjuvant therapy, the efficacy of the therapy and the feasibility of radical D2 resection are assessed through imaging examinations. Efficacy evaluation is performed within 2 weeks of the completion of neoadjuvant therapy, and radical gastrectomy is performed within 4-6 weeks. Postoperative treatment is determined jointly by the clinician and the patient based on actual clinical practice. The primary endpoint is complete pathological response (pCR) rate, defined as the proportion of subjects who have no residual surviving tumor cells under microscopic examination and are negative for lymph nodes. Safety assessment: Safety assessments are performed after each cycle of neoadjuvant therapy and 30 days postoperatively. Event follow-up: Follow-up events are then conducted every 3 months for the first year postoperatively, and every 6 months for 1-2 years, up to 2 years postoperatively.
• Voluntary written informed consent provided.
• Age ≥ 18 years and ≤ 75 years at enrollment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2.
• Life expectancy ≥ 6 months.
• Diagnosis of gastroesophageal junction (GEJ) adenocarcinoma by gastroscopy and histopathology. According to AJCC 8th edition staging, abdominal CT assessment confirms clinical stage cStage III (cT3-4aN1-3M0). For GEJ cancers, only Siewert type III and those Siewert type II cases not requiring combined thoracotomy are eligible.
• Prior to enrollment, a multidisciplinary assessment involving at least one gastrointestinal surgery attending physician and one radiologist confirms cStage III disease, eligibility for R0 resection with curative intent, patient's agreement to undergo radical surgery, and absence of surgical contraindications as judged by the surgeon.
• No prior systemic anti-cancer therapy for the current disease, including surgery, radiotherapy, chemotherapy, immunotherapy, etc.
• Adequate cardiac function to undergo curative-intent resection. Patients with underlying ischemic, valvular, or other significant heart disease should undergo preoperative evaluation by a cardiologist if clinically indicated.
• Adequate organ function, meeting the following laboratory parameters (without supportive measures within specified timeframes):
‣ Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L (without granulocyte colony-stimulating factor support within 14 days).
⁃ Platelets ≥100 × 10⁹/L (without transfusion within 14 days).
⁃ Hemoglobin \>8 g/dL (without transfusion or erythropoietin use within 14 days).
⁃ Total bilirubin ≤1.5 × upper limit of normal (ULN); OR total bilirubin \>1.5 × ULN but direct bilirubin ≤ ULN.
⁃ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN.
⁃ Serum creatinine ≤1.5 × ULN AND calculated creatinine clearance (Cockcroft-Gault formula) ≥60 mL/min.
⁃ Adequate coagulation, defined as International Normalized Ratio (INR) or prothrombin time (PT) ≤1.5 × ULN.
⁃ Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within normal range. If baseline TSH is outside normal range, subjects with total T3 (or FT3) and FT4 within normal range are eligible.
⁃ Myocardial enzymes within normal limits (subjects with isolated lab abnormalities judged by the investigator as clinically insignificant may be eligible).
⁃ For female patients:
∙ Postmenopausal (defined as ≥1 year of amenorrhea without an alternative cause), OR surgically sterilized (removal of ovaries and/or uterus), OR, if of childbearing potential, must meet all the following:
⁃ Negative pregnancy test within 7 days prior to first dose.
• Agreement to use highly effective contraception (annual failure rate \<1%) or practice abstinence from heterosexual intercourse from signing informed consent until at least 120 days after last dose of investigational product and at least 9 months after surgery. Highly effective methods include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
‣ Must not be breastfeeding.
⁃ For male patients: Agreement to practice abstinence from heterosexual intercourse or use contraception with the following details: If partner is a woman of childbearing potential or is pregnant, the male patient must remain abstinent or use a condom from signing informed consent until at least 120 days after last dose of investigational product and at least 9 months after surgery. The reliability of sexual abstinence should be evaluated considering the study duration and the patient's preferences and lifestyle. Periodic abstinence (calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods.
⁃ The subject has read and fully understands the patient information, and has signed the informed consent form.