An Umbrella-designed Prospective Multicenter Randomized Open-label Superiority Trial Evaluating Multi-biomarker-guided Precision Therapy for First-line Treatment of Advanced Esophageal Squamous Cell Carcinoma

Inclusion Criteria:

1. Aged between 18 and 75 years (calculated on the date of signing the informed consent form);
2. Patients with metastatic esophageal squamous cell carcinoma (ESCC) confirmed by histopathology or cytology;
3. Treatment-naïve patients with no prior anti-tumor therapy;
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, with an expected survival of more than 3 months;
5. Judged by the investigator to be suitable for first-line chemotherapy;
6. Presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1);

7. Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, condoms) throughout the study period and for 6 months after the end of study treatment; they must have a negative serum or urine pregnancy test within 7 days prior to enrollment and shall not be breastfeeding. Male patients must agree to use effective contraception throughout the study period and for 6 months after the end of study treatment.

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8. Voluntarily participate in this study and provide written informed consent.

Exclusion Criteria:

1. Brain metastases with symptoms or symptom control duration less than 2 months;
2. History of or concurrent other malignant tumors within the past 3 years (excluding cured basal cell carcinoma of the skin and carcinoma in situ of the cervix);

3. Insufficient bone marrow hematopoietic function (without blood transfusion within 14 days):

   1. Absolute Neutrophil Count (ANC) < 1.5 × 10⁹/L;
   2. Platelet count < 100 × 10⁹/L;
   3. Hemoglobin < 90 g/L.

4. Hepatic abnormalities:

   1. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) or Alkaline Phosphatase (ALP) > 2.5 × Upper Limit of Normal (ULN) in patients without liver metastases; ALT, AST or ALP > 5 × ULN in patients with liver metastases;
   2. Serum total bilirubin > 1.5 × ULN (> 3 × ULN for patients with Gilbert's syndrome);
   3. Decompensated liver cirrhosis (Child-Pugh liver function grade B or C);
   4. Positive Hepatitis B Surface Antigen (HBsAg) with Hepatitis B Virus (HBV) DNA load ≥ 2000 IU/mL. Patients with positive HBsAg and HBV DNA load < 2000 IU/mL must receive anti-HBV therapy for at least 2 weeks prior to the first study drug administration;
   5. Positive Hepatitis C Virus (HCV) antibody with detectable HCV RNA.

5. Renal abnormalities:

   1. Serum creatinine > 1.5 × ULN or estimated creatinine clearance < 60 mL/min calculated by the Cockcroft-Gault formula;
   2. Urinalysis showing urine protein ≥ ++, confirmed with 24-hour urinary protein quantification > 1.0 g;
   3. Renal failure requiring hemodialysis or peritoneal dialysis;
   4. Medical history of nephrotic syndrome.

6. Bleeding risks:

   1. Abnormal coagulation function: Activated Partial Thromboplastin Time (APTT) or Thrombin Time (TT) > 1.5 × ULN, or International Normalized Ratio (INR) > 1.5 (> 2.5 for subjects receiving anticoagulant therapy);
   2. History of hemorrhage (hemoptysis), coagulopathy, or ongoing use of warfarin, aspirin, low-molecular-weight heparin and other antiplatelet drugs (except prophylactic aspirin at a dose ≤ 100 mg/day);
   3. Any signs or history of bleeding diathesis regardless of severity;
   4. Active gastrointestinal bleeding defined as hematemesis, hematochezia or melena within the past 3 months without evidence of resolution confirmed by gastroscopy or colonoscopy;
   5. Any Grade ≥ 3 bleeding event per CTCAE occurring within 4 weeks prior to the first study drug administration.

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7. Cardiovascular and cerebrovascular abnormalities:

   1. Subjects with any of the following conditions within 12 months before the first study drug administration: grade ≥ II myocardial ischemia or myocardial infarction, arrhythmia, grade ≥ III cardiac insufficiency, uncontrolled angina, coronary/peripheral artery bypass graft surgery, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, etc.;
   2. Deep vein thrombosis or pulmonary embolism occurring within 6 months before the first study drug administration;
   3. Left Ventricular Ejection Fraction (LVEF) < 50% assessed by Doppler echocardiography;
   4. Average Fridericia-corrected QT interval (QTcF) (from at least 3 consecutive electrocardiograms): ≥ 450 ms for male patients, ≥ 470 ms for female patients;
   5. Uncontrolled hypertension refractory to medication (systolic blood pressure ≥ 150 mmHg and diastolic blood pressure ≥ 100 mmHg recorded in at least two measurements).

8. History of immunodeficiency:

   1. Confirmed Human Immunodeficiency Virus (HIV) infection;
   2. Other acquired or congenital immunodeficiency disorders;
   3. Scheduled or prior solid organ transplantation, hematopoietic stem cell transplantation within 60 days before the first study drug administration, or significant graft-versus-host disease;
   4. Patients requiring immunosuppressants, systemic or absorbable local hormonal therapy for immunosuppressive purposes that must be continued within 7 days before the first study drug administration (excluding daily glucocorticoid dose < 10 mg prednisone or equivalent steroids).
9. Active or uncontrolled severe infection (Grade ≥ 2 per CTCAE);
10. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage (judged by the investigator);
11. Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA-4 antibody, or any other antibodies targeting T cell co-stimulatory or checkpoint pathways (e.g., OX40, CD137, etc.);
12. Complicated with severe or poorly controlled diseases judged by the investigator to carry substantial risks for study participation (e.g., poorly controlled diabetes with screening fasting plasma glucose (FPG) > 10 mmol/L);
13. Participation in another clinical trial of anti-tumor agents within 28 days prior to screening.