Overview

This is a multicenter Phase 1b/2 clinical trial investigating the efficacy and safety of a combination regimen of Gemcitabine, Cisplatin, Nab-paclitaxel, and Tislelizumab in treatment-naïve patients with unresectable, locally advanced, or metastatic biliary tract cancers (BTC), including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

The Phase 1b portion aims to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of Nab-paclitaxel in combination with Gemcitabine, Cisplatin, and Tislelizumab. In the Phase 2 portion, the study will evaluate the Objective Response Rate (ORR) as the primary endpoint, with additional assessments of Overall Survival (OS), Progression-Free Survival (PFS), Disease Control Rate (DCR), and Quality of Life (QoL). Safety and tolerability will also be closely monitored.

This study seeks to leverage the stromal-disrupting effect of Nab-paclitaxel and the immune checkpoint blockade effect of Tislelizumab, combined with the established chemotherapy backbone of Gemcitabine and Cisplatin, to enhance treatment outcomes for BTC patients. The study will enroll patients across three medical centers in South Korea, including CHA Bundang Medical Center, Haeundae Paik Hospital, and Seoul National University Bundang Hospital.

Eligibility

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