Exploration of Sintilimab + Bevacizumab + AG Chemotherapy as First-Line Treatment for Unresectable Advanced/Metastatic Cholangiocarcinoma

This study is a single-arm, Phase II clinical trial evaluating the efficacy and safety of Sintilimab plus Bevacizumab and the AG regimen as first-line therapy in patients with surgically ineligible locally advanced or metastatic cholangiocarcinoma.

After providing informed consent, patients receive:

Sintilimab: 200 mg IV Q3W Bevacizumab: 15 mg/kg IV Q3W AG Chemotherapy: Nab-paclitaxel + Gemcitabine for 8 cycles.

Post-chemotherapy, patients continue Sintilimab + Bevacizumab maintenance until:

Disease progression Death Intolerable toxicity Withdrawal of consent Initiation of new antitumor therapy Other protocol-specified reasons (Maximum treatment duration: 24 months)

Inclusion criteria

• Signed written informed consent prior to any trial-related procedures.
• Male or female aged **≥18 years and ≤75 years**.
• Histologically or cytologically confirmed, surgically unresectable locally advanced or metastatic cholangiocarcinoma.
• No prior systemic therapy; subjects who completed postoperative adjuvant therapy **>6 months ago** are eligible.
• Life expectancy >3 months.
• At least one measurable lesion per RECIST 1.1 criteria.
• ECOG PS score 0 or 1.
• Adequate organ function (all laboratory criteria below must be met):

（1）Absolute neutrophil count (ANC) **≥1.5×10⁹/L** without granulocyte colony-stimulating factor within 14 days; （2）Platelets **≥90×10⁹/L** without transfusion within 14 days; （3）Hemoglobin **>9 g/dL** without transfusion/recombinant erythropoietin within 14 days; （4）Total bilirubin ≤1.5×ULN; （5）AST/ALT ≤2.5×ULN (≤5×ULN allowed if liver metastases present); （6）Serum creatinine ≤1.5×ULN AND creatinine clearance (Cockcroft-Gault formula) **≥60 mL/min**; （7）INR or PT ≤1.5×ULN; （8）TSH within normal range; OR if abnormal, total T3 (or FT3) AND FT4 within normal limits; （9）Cardiac enzymes within normal limits (isolated abnormalities deemed clinically insignificant by investigator are allowed).

• For women of childbearing potential:

（1）Negative urine/serum pregnancy test within 3 days before Cycle 1 Day 1 (confirm equivocal urine tests with serum testing).

（2）Non-childbearing potential defined as:

• Postmenopausal (≥1 year amenorrhea), OR
• Surgically sterilized/hysterectomy. 10. All subjects (regardless of gender) at conception risk must use contraception with <1% annual failure rate during treatment and for 120 days after last dose.

Exclusion criteria

• Other malignancies within 5 years prior to first dose (excluding radically cured basal cell carcinoma, squamous cell carcinoma of skin, or carcinoma in situ).
• Current participation in interventional clinical trials or receipt of other investigational drugs/devices within 4 weeks before first dose.
• Prior therapy with:

<!-- -->

• Anti-PD-1/PD-L1/PD-L2 agents;
• Drugs targeting stimulatory/co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137).

• Systemic administration of antitumor Chinese herbal medicines or immunomodulators (e.g., thymosin, interferon, interleukin) within 2 weeks (except localized use for pleural effusion).

• Active autoimmune disease requiring systemic treatment within 2 years (e.g., disease-modifying drugs, corticosteroids ≥10 mg/day prednisone equivalent, immunosuppressants).
• Exclusions: Hormone replacement (thyroxine/insulin/physiologic steroids);
• Known primary immunodeficiency;
• Isolated autoantibody positivity requires investigator confirmation of no autoimmune disease.

• Systemic glucocorticoids (excluding topical/inhaled) or immunosuppressive therapy within 4 weeks.Note: Physiologic-dose steroids (≤10 mg/day prednisone equivalent) permitted.

• Prior anti-angiogenic therapy (e.g., bevacizumab). 8. Active bleeding within 3 months prior to first dose:
• Hemoptysis (≥2.5 mL/fresh blood episode);
• Gastrointestinal bleeding. 9. High bleeding risk: Tumor invasion of major vessels or radiologist/investigator-assessed bleeding tendency.

• Major surgery within 4 weeks (excluding biopsy). 11. Severe unhealed wounds/ulcers/fractures. 12. Aspirin (>325 mg/day) or platelet-inhibiting NSAIDs for >10 consecutive days within 10 days prior to first dose.

• Full-dose anticoagulants/thrombolytics for >10 consecutive days within 10 days prior to first dose.Note: Prophylactic low-dose anticoagulants allowed:

（1）Warfarin ≤1 mg/day (INR ≤1.5); （2）Heparin ≤12,000 U/day; （3）Aspirin ≤100 mg/day. 14. Hereditary bleeding disorders, coagulopathy, or thrombotic history. 15. Clinically uncontrolled pleural effusion/ascites (asymptomatic/minimal fluid without drainage allowed).

• Allogeneic organ transplant (excluding corneas) or hematopoietic stem cell transplant.

• Hypersensitivity to sintilimab/bevacizumab or excipients. 18. Inadequate recovery from prior intervention toxicities (i.e., >Grade 1 or not returned to baseline, excluding alopecia/fatigue).

• HIV infection (HIV 1/2 antibody-positive). 20. Untreated active HBV:
• HBsAg-positive AND HBV-DNA > local ULN;
• Exceptions:

a. HBV-DNA <500 IU/mL with ongoing antiviral therapy; b. Anti-HBc (+) only with HBV-DNA monitoring. 21. Active HCV infection (HCV antibody-positive AND detectable HCV-RNA). 22. Live attenuated vaccines within 4 weeks prior to first dose. 23. Pregnancy or breastfeeding. 24. Uncontrolled systemic diseases, including:

• Severe uncontrolled cardiac arrhythmias (e.g., complete LBBB, ≥Grade II AV block, VT/AF);
• Unstable angina, CHF, NYHA Class ≥II heart failure;
• Arterial thromboembolism within 6 months (e.g., MI, stroke, TIA);
• Major surgery/unhealed wounds within 4 weeks; biopsy within 7 days (except IV catheterization);
• Uncontrolled hypertension (>140/90 mmHg);
• Active tuberculosis;
• Uncontrolled systemic infection;
• Clinical diverticulitis, intra-abdominal abscess, GI obstruction;
• Decompensated liver disease/active hepatitis;
• Uncontrolled diabetes (fasting glucose >10 mmol/L);
• Urine protein ≥++ AND 24-hr urine protein >1.0 g. 25. Psychiatric disorders impairing treatment compliance. 26. Any condition that may:

（1）Interfere with trial results; （2）Prevent full study participation; （3）Pose additional risks (per investigator judgment).