Combination Therapy of GCNT and Tislelizumab in Advanced Biliary Tract Cancer

Prior treatment

• 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
• Unresolved toxicities from prior treatment that could affect study evaluation
• 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
• 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)
• Use of unapproved drugs within 28 days before enrollment

Other illness

• 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
• 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 diabetes mellitus
• Positive for:
  • HIV-1 or HIV-2
  • Active Hepatitis B or C (except HBV DNA \<500 IU/mL with stable antiviral therapy)
• Cognitive impairment preventing informed consent
• Hearing impairment

Other

• Uncontrolled tumor-related complications: Pericardial effusion, pleural effusion, or ascites requiring intervention, Uncontrolled tumor-related pain
• Pregnant or breastfeeding women
• Severe neuropathy (Grade ≥ 2, CTCAE v5.0)
• Inability or unwillingness to provide informed consent

• 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).