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

Korábbi kezelés

• 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:
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• Exclusions: Hormone replacement (thyroxine/insulin/physiologic steroids);
• Isolated autoantibody positivity requires investigator confirmation of no autoimmune disease.
  • 6\. Systemic glucocorticoids (excluding topical/inhaled) or immunosuppressive therapy within 4 weeks.Note: Physiologic-dose steroids (≤10 mg/day prednisone equivalent) permitted.
  • 7\. Prior anti-angiogenic therapy (e.g., bevacizumab). 8. Active bleeding within 3 months prior to first dose:
• 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:
• Major surgery/unhealed wounds within 4 weeks; biopsy within 7 days (except IV catheterization);

Más betegség

• Drugs targeting stimulatory/co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137).
  • 4\. Systemic administration of antitumor Chinese herbal medicines or immunomodulators (e.g., thymosin, interferon, interleukin) within 2 weeks (except localized use for pleural effusion).
  • 5\. Active autoimmune disease requiring systemic treatment within 2 years (e.g., disease-modifying drugs, corticosteroids ≥10 mg/day prednisone equivalent, immunosuppressants).
• 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);
• Uncontrolled hypertension (\>140/90 mmHg);
• Active tuberculosis;
• Uncontrolled systemic infection;
• Decompensated liver disease/active hepatitis;
• 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).

Laborértékek

• Gastrointestinal bleeding. 9. High bleeding risk: Tumor invasion of major vessels or radiologist/investigator-assessed bleeding tendency.
  • 10\. 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.
  • 13\. 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).
  • 16\. Allogeneic organ transplant (excluding corneas) or hematopoietic stem cell transplant.
  • 17\. 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).
  • 19\. HIV infection (HIV 1/2 antibody-positive). 20. Untreated active HBV:
• HBsAg-positive AND HBV-DNA \> local ULN;
• Uncontrolled diabetes (fasting glucose \>10 mmol/L);

Egyéb

• Anti-PD-1/PD-L1/PD-L2 agents;
• Known primary immunodeficiency;
• Hemoptysis (≥2.5 mL/fresh blood episode);
• Exceptions:
• Clinical diverticulitis, intra-abdominal abscess, GI obstruction;

• 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).
  • 9\. 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.