Efficacy and Safety of SBRT Plus Gemcitabine, Cisplatin, and Sintilimab as First-Line Treatment for Unresectable Biliary Tract Cancer

Evaluation of the Efficacy and Safety of Stereotactic Body Radiotherapy (SBRT) Combined With Gemcitabine, Cisplatin, and Sintilimab as First-Line Therapy for Unresectable Biliary Tract Cancer: A Prospective, Multicenter, Randomized Controlled Study

According to current clinical guidelines, first-line treatment for advanced biliary tract cancer (BTC) is the gemcitabine plus cisplatin (GC) regimen combined with immunotherapy, which has been shown to improve patient outcomes. Additionally, the combination of radiotherapy and immunotherapy may synergistically enhance antitumor efficacy. Therefore, this study aims to assess the efficacy and safety of first-line treatment with radiotherapy in combination with sintilimab and gemcitabine/cisplatin versus sintilimab in combination with gemcitabine/cisplatin in patients with previously untreated, unresectable locally advanced or metastatic BTC.

Inclusion Criteria:

1. Patients voluntarily provide written informed consent, with authorization obtained from the patient or legal representative prior to any protocol-related procedures.

2. Age ≥ 18 years and ≤ 75 years; both female and male

3. Histologically or cytologically confirmed, unresectable advanced or metastatic adenocarcinoma of biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma.

4. No prior systemic anti-tumor treatment for BTC. Patients who developed recurrent disease >6 months after surgery with curative intent and, if given, >6 months after the completion of neo/adjuvant therapy (chemotherapy and/or radiation) will be eligible.

5. At least 1 lesion that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline.

6. ECOG performance status of 0 or 1.

7. Life expectancy ≥12 weeks.

8. Adequate organ and bone marrow function within 14 days prior to initiation of study treatment, defined as follows:

   a.Hematology (without transfusion, granulocyte colony-stimulating factor [G-CSF], or other correction treatment within 14 days prior to screening): i.Hemoglobin [HB] ≥ 90 g/L; ii.Absolute neutrophil count [ANC] ≥ 1.5 × 109/L; iii.platelet count (PLT) ≥ 75 × 109/L b.Biochemistry Examination (without albumin infusion within 14 days prior to screening): i.Total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) (for patients with Gilbert's syndrome, ≤ 3 × ULN) ii.alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN; for patients with liver metastases, ALT and AST ≤ 5 × ULN; iii.serum creatinine (Cr) ≤ 1.5 × ULN or clearance of creatinine (CCr) ≥ 50 mL/min (Cockcroft-Gault formula);

   • Male: Creatinine clearance rate = [(140 - age) × weight] / (72 × serum Cr)
   • Female: Creatinine clearance rate= [(140 - age) × weight] / (72 × serum Cr) × 0.85 (Weight unit: kg; serum Cr unit: mg/dL)

9. Patients with evidence of hepatitis B virus (HBV) infection, defined as detectable HBV DNA (≥10 IU/mL or above the lower limit of detection according to local laboratory standards) and positive HBsAg and/or anti-HBc, must receive antiviral therapy prior to study drug administration in accordance with institutional practice to ensure adequate viral suppression. Antiviral therapy must be continued throughout the study period and for at least 6 months after the last dose of study treatment. Patients who are anti-HBc positive but HBV DNA negative (<10 IU/mL or below the lower limit of detection according to local laboratory standards) are not required to receive antiviral therapy unless HBV DNA rises to ≥10 IU/mL or exceeds the local lower limit of detection during study treatment.

10. Female patients of childbearing age must have a documented negative urine or serum pregnancy test within 7 days prior to the first dose. If the urine test result is inconclusive, a serum test must be performed, and the serum result will be considered definitive. Female patients of childbearing age who have sexual intercourse with non-sterilized male partners must agree to take effective contraceptive measures throughout the treatment and 120 days after the last dose.

11. Male patients with female sexual partners of childbearing age must agree to take effective contraceptive measures throughout the treatment and 120 days after the last dose. The decision to discontinue contraception beyond this time frame should be discussed with the investigator.

12. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study requirements.

Exclusion Criteria:

1. Histologically or cytologically confirmed rare biliary tract tumors, including ampullary cancer, neuroendocrine tumors, sarcoma, or mucinous cystic neoplasms.

2. Other active malignancy within the past 5 years or concurrent, except adequately treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin.

3. History of carcinomatous meningitis or brain metastases.

4. Known hypersensitivity or allergic reaction to any study drug or any excipient therein.

5. Participation in another investigational drug clinical trial within the past 3 months or concurrent enrollment in another clinical study, unless observational, non-interventional, or follow-up phase of an interventional study.

6. Uncontrolled concurrent illness, including but not limited to moderate to severe ascites, uncontrolled or moderate-to-large pleural or pericardial effusion, uncontrolled acute or chronic pancreatitis, active hemorrhagic disorder, or severe chronic gastrointestinal disease associated with diarrhea.

7. History of allogeneic organ or allogeneic bone marrow transplantation.

8. History of significant cardiovascular or cerebrovascular disease, including:

   1. congestive heart failure (NYHA Class ≥II), unstable angina, myocardial infarction, uncontrolled arrhythmia, or cerebrovascular accident within 12 months prior to first dose;
   2. left ventricular ejection fraction <50%;
   3. corrected QT interval (QTc) >480 ms (Fridericia formula);
   4. poorly controlled hypertension (systolic ≥150 mmHg or diastolic ≥100 mmHg based on ≥2 measurements);
   5. history of hypertensive crisis or hypertensive encephalopathy.

9. Active autoimmune disease within 2 years prior to first dose or history of autoimmune disease with potential for relapse, including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, colitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism (except hypothyroidism controlled by hormone replacement therapy).

10. Prior anti-cancer therapy-related adverse events not recovered to Grade ≤1 or baseline, with Grade ≤2 neuropathy possibly eligible per investigator assessment.

11. Active infection, including tuberculosis or human immunodeficiency virus (HIV).

12. Diagnosis of immunodeficiency, or chronic systemic steroid therapy (daily dose >10 mg prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to first dose of study intervention.

13. History of gastrointestinal bleeding within 6 months prior to study treatment, documented predisposition to gastrointestinal hemorrhage, or known hereditary or acquired bleeding (e.g., coagulopathy) or thrombotic tendency.

14. Major surgery (excluding biopsy) with incomplete recovery from surgery or surgical complications, or incomplete wound healing, prior to start of study intervention, or anticipated need for major surgery during the study period.

15. Receipt of live attenuated vaccine within 28 days prior to first dose of study intervention, or anticipated need for live attenuated vaccine during study treatment or within 60 days after last dose.

16. Any other condition judged by the investigator to potentially interfere with study outcomes or lead to premature study termination, including alcohol or drug abuse, severe comorbidity requiring concomitant therapy (including psychiatric illness), severe laboratory abnormality, or family or social factors affecting patient safety or data collection.