Combination Therapy of GCNT and Tislelizumab in 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