Combination therapy for advanced biliary tract cancer

Inclusion Criteria

* Histologically confirmed biliary tract cancer (BTC), including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer (excluding neuroendocrine tumors, sarcoma, mixed cholangiocarcinoma-HCC, and ampullary carcinoma).
* Age ≥ 19 years at the time of signing informed consent.
* Treatment-naïve for unresectable or metastatic BTC, or recurrence/metastasis at least 6 months after curative surgery or adjuvant chemotherapy.
* Measurable lesions per RECIST v1.1.
* ECOG Performance Status (PS) of 0-1 within 14 days prior to the first dose.
* Life expectancy of ≥ 3 months.
* Adequate organ function (within 14 days prior to the first dose):

  * Hematologic function: Hemoglobin (Hb) ≥ 9.0 g/dL, Absolute neutrophil count (ANC) ≥ 1,500/μL, Platelet count ≥ 100,000/μL
  * Renal function: Serum creatinine ≤ 1.5 × ULN or CrCl (Cockcroft-Gault) ≥ 45 mL/min
  * Hepatic function: AST and ALT ≤ 3.0 × ULN (≤ 5.0 × ULN for hepatic metastases), Total bilirubin ≤ 1.5 × ULN
  * Coagulation: INR ≤ 1.5 or prothrombin time ≤ 1.5 × ULN, aPTT ≤ 1.5 × ULN
* Reproductive status:

  * Female participants must provide proof of non-childbearing status or a negative serum pregnancy test within 7 days before the first dose.
  * Female subjects receiving cisplatin must agree to effective contraception for 14 months after the last dose; male subjects must agree for 11 months.
  * Women of childbearing potential and non-sterilized men must use at least two effective contraceptive methods during the study and for 6 months after the last dose.
* Cardiac function:

  * Left ventricular ejection fraction (LVEF) ≥ 50% (by echocardiography or MUGA scan)
  * No serious valvular disorders or arrhythmias
  * Corrected QT interval ≤ 470 msec at screening
* Willingness to provide tumor tissue samples by biopsy (endoscopic or excisional).

Exclusion Criteria

* Prior treatment history:

  * Prior systemic chemotherapy, biological therapy, immunotherapy, or hormone therapy for unresectable or metastatic BTC
  * Prior adjuvant chemotherapy or radiation therapy within 6 months before recurrence
* History of another malignancy within 5 years, except:

  * Completely resected basal cell carcinoma, stage 1 squamous cell carcinoma, carcinoma in situ, or superficial bladder cancer
* Unresolved toxicities from prior treatment that could affect study evaluation
* Known hypersensitivity to any study drug (tislelizumab, gemcitabine, cisplatin, nab-paclitaxel)
* Active or history of autoimmune disease, except:

  * Hypothyroidism (on stable hormone therapy), vitiligo, or psoriasis not requiring treatment
* History of interstitial lung disease, pulmonary fibrosis, or radiation pneumonitis
* Active gastrointestinal disease:

  * Active peptic ulcer, colitis, or diverticulitis Known central nervous system (CNS) metastasis
* Uncontrolled tumor-related complications: Pericardial effusion, pleural effusion, or ascites requiring intervention, Uncontrolled tumor-related pain
* Significant cardiovascular conditions:

  * Myocardial infarction within 180 days before enrollment
  * Uncontrolled angina within 180 days before enrollment
  * NYHA Class III or IV congestive heart failure
  * Persistent hypertension ≥ 150/90 mmHg despite treatment
  * Arrhythmias requiring medical intervention
  * Thrombosis or vascular diseases requiring surgery
* Uncontrolled diabetes mellitus
* Active infections requiring systemic treatment within 14 days before the first dose
* Recent treatment history:

  * Systemic corticosteroids (except prophylactic or short-term use) or immunosuppressants within 28 days before the first dose
  * Antitumor therapy (cytotoxic, targeted, or immunotherapy) within 28 days before the first dose
  * Pleurodesis within 28 days before the first dose
  * Major surgery under general anesthesia within 28 days before the first dose
  * Local anesthesia or minor surgery within 14 days before the first dose
  * Radiation therapy within 28 days before the first dose (bone metastasis radiation within 14 days is allowed)
* Positive for:

  * HIV-1 or HIV-2
  * Active Hepatitis B or C (except HBV DNA \<500 IU/mL with stable antiviral therapy)
* Pregnant or breastfeeding women
* Use of unapproved drugs within 28 days before enrollment
* Cognitive impairment preventing informed consent
* Severe neuropathy (Grade ≥ 2, CTCAE v5.0)
* Hearing impairment
* Inability or unwillingness to provide informed consent