Neoadjuvant Tislelizumab, Gemcitabine, Cisplatin and S-1 for Resectable High-risk Cholangiocarcinoma

Patients with cholangiocarcinoma have limited therapeutic options and a poor prognosis. Margin-free resection is the only curative treatment to treat intrahepatic cholangiocarcinoma (iCCA). However, patients with resectable disease still suffer from high recurrence or progression. Both immune checkpoint inhibitors and chemotherapy have shed light on treating patients with iCCA. Nevertheless, the role of neoadjuvant chemo-immunotherapy has not been established in patients with resectable iCCA harboring a high risk for recurrence. The aim of the trial is to investigate the efficacy and tolerability of neoadjuvant tislelizumab, gemcitabine, cisplatin and S-1 (Tis-GCS) in patients with resectable high-risk iCCA. The primary outcome is R0 resection rate. The secondary outcome includes objective response rate, event-free survival, overall survival, protocol completion rate and adverse events. The study is an open-label, single-arm and multi-center phase II investigator-initiated trial with Simon two-stage design. Subjects with resectable iCCA harboring a high risk for recurrence or those suffer from very early recurrent disease who are eligible for a curative resection are included. A total of 35 subjects are expected with a minimal sample size of 14 when the R0 resection rate is of the lower threshold. Tis-GCS (14 days as a cycle) 3 cycles every 2 weeks will be administered and followed by surgery. Tislelizumab 200 mg fixed-dose, gemcitabine 800 mg/m2 and cisplatin 25 mg/m2 is given intravenously on day 1. S-1 (35 mg/m2) is given twice daily per oral on day 1 to 7. The study will prove the feasibility and efficacy of neoadjuvant chemo-immunotherapy in resectable high-risk iCCA. The results may provide critical fundamentals into future phase III clinical trials.

Inclusion criteria

• Subjects must meet the criteria of either (A) or (B), plus 1. to 6. (A) High-risk group (HR) Subjects have histologically-confirmed and potentially resectable intrahepatic cholangiocarcinoma, according to the definition of American Joint Cancer Committee staging system, 8th edition (AJCC 8th).

Plus at least one of the following high-risk features,

• Solitary tumor with a maximal diameter ≥5 cm in the absence of vascular invasion.
• ≥T1b disease which is resectable.
• Multifocal tumors or single tumor with satellite nodules at the same anatomic liver lobe which is/are resectable.
• Tumor(s) with macroscopic intrahepatic vascular invasion but is/are potentially resectable.
• Image or histological evidence of hilar or portal lymph node involvement (N1).
• Initial serum cancer antigen-199 (CA199) ≥200 U/mL.

(B) Very early recurrence group (VER) Subjects with previously resected cholangiocarcinoma under a curative intent and have an early recurrent disease (≤6 months post curative surgery) confined to the liver, with/without antecedent adjuvant local or systemic therapies, and can be re-resected under a curative intent.

• Subjects present with at least one measurable lesion which can be accurately assessed by conventional techniques at least 1.0 cm by computed tomography (CT) or magnetic resonance imaging (MRI).
• Subjects are above 18 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1, have a life expectancy >3 months, have surgically resectable disease and are physically competent and willing to receive a curative operation following the study protocol
• Subjects have adequate organ functions, including bone marrow reserve with a leukocyte count ≥3,000 /µL and platelet count ≥50,000 /µL, hepatic reserve with a serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin ≤3 times of upper normal testing limits (biliary drainage is permitted), renal reserve with a creatinine clearance ≥60 mL/min and cardiac reserve with a New York Heart Association (NYHA) functional classification I at baseline.
• Subjects have or agree to establish a vascular access that permits intravenous administration of medications and are capable of ingesting capsules per oral.
• Subjects with reproductive potentials are willing to accept contraceptive measures during the trial.
• Subjects are functionally and cognitively capable to be informed of the trial contents and objectives (including obtaining blood and tumor tissue for the trial investigation), and agree to sign the written consent for enrollment.

Exclusion criteria

• Subjects have metastatic (M1) disease, recurrent cholangiocarcinoma which cannot be resected, recurrent cholangiocarcinoma which can be re-resected but occurs >6 months post previous surgery, or any other primary malignancies in which the subjects have been in disease-free status less than 2 years, excluding carcinoma in situ or resectable skin cancer.
• Subjects have received a systemic therapy with either chemotherapeutics or immune checkpoint inhibitors, a major abdominal surgery or radiotherapy within 4 weeks before the trial enrollment.
• Subjects are known to be severely allergic to any of the studied therapeutics.
• Subjects have underlying chronic illnesses, including cardiopulmonary diseases, ischemic heart disease, inflammatory bowel disease, poorly-controlled diabetes mellitus, liver cirrhosis and/or debilitating autoimmune diseases or conditions.

5 Subjects are receiving or have received a systemic administration of an equivalent dose of daily 10 mg prednisone or above for ≥14 days in whatever indications within 4 weeks before the trial enrollment, or immunosuppressives for ≥7 days within 4 weeks before the trial enrollment.

• Subjects have active bacterial, viral, fungal or mycobacterial infections that require systemic therapy, including active infection with human immunodeficiency virus (HIV), hepatitis B or C virus (HBV or HCV).

• Subjects are planning to conceive or already in pregnancy or breastfeeding. 8. Subjects are currently participating in any other clinical trials or studies which potentially interfere the protocol commencement.