A Clinical Trial Evaluating the Safety and Efficacy of Intravenous HNF4α srRNA in Treating Advanced ICC Patients

A Clinical Trial Assessing the Safety and Efficacy of Intravenous HNF4α srRNA for the Treatment of Patients With Advanced Intrahepatic Cholangiocarcinoma

The goal of this investigator-initiated, a single-arm, open-label, pilot study is to investigate the safety, tolerability, and efficacy of intravenous HNF4α srRNA treatment in subjects with advanced Intrahepatic Cholangiocarcinoma (ICC).

Condition of disease: advanced intrahepatic cholangiocarcinoma Intervention： HNF4α srRNA will be administered intravenously for the treatment of ICC. The dosing regimen is planned for a second dose 14 ± 3 days post-initial treatment, followed by subsequent treatments every 28 ± 7 days, with adjustments made based on patient tolerance and therapeutic response. This is a dose escalation assay employing a i3+3 design to assess escalating HNF4α srRNA dosages: 25 μg, 50 μg, and 100 μg. Post-initial dose, a 14-day dose-limiting toxicities (DLT) observation will evaluate tolerability and safety, guiding dose adjustments or selection of the Recommended Dose (RD) for the expansion phase. Cohorts may include up to 9 participants, adjusted for safety.

Drug: HNF4α srRNA, a drug specifically designed to target liver cancer cells and facilitate the expression of HNF4α.

According to Amendment 1, patients who have received at least 4 cycles of HNF4α srRNA therapy and have a tumor assessment of SD (stable disease) or PD (progressive disease) per RECIST v1.1 criteria may, after a comprehensive evaluation by the investigator considering the patient's treatment history and the current safety and efficacy data of HNF4α srRNA, continue HNF4α srRNA at the same dose, or have their dose adjusted, in combination with immunotherapy, targeted therapy, or chemotherapy.

Inclusion Criteria:

1. Males or females, aged 18 years or older.
2. Histologically or cytologically confirmed intrahepatic cholangiocarcinoma patients.
3. Patients with intrahepatic cholangiocarcinoma not suitable for surgical resection, liver transplantation, or ablation therapy, or those with post-surgical recurrence and/or metastasis.
4. Patients not suitable for local or systemic treatment, or those who have progressed after at least one chemotherapy regimen containing gemcitabine/fluoropyrimidine/platinum, etc..
5. Life expectancy of 12 weeks or more.
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2.
7. Males with fertility and females of childbearing potential are willing to use a highly effective method of contraception for the entire study period and for 6 months after study drug discontinuation. Females of childbearing age, including premenopausal females and within 2 years after menopause, must have a negative serum pregnancy test result within 7 days prior to the first dose of study treatment.
8. Subjects who had a voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

Exclusion Criteria:

• Patients with any of the following criteria were excluded from participation in this study

  1. Inadequate liver function：Albumin (ALB) < 25 g/L, or total bilirubin > 5 × the upper limit of normal (ULN), or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or alanine aminotransferase (ALT) >10 × ULN.
  2. Inadequate renal function defined as creatinine >1.5 × ULN or calculated creatinine clearance < 40 mL/min.
  3. Absolute neutrophil count (ANC) < 1.0×109/L, or Platelets < 30×109/L, or Hemoglobin < 8.5 g/dL.
  4. International normalized ratio (INR) > 2.3.
  5. Poorly controlled hypertension, diabetes or other serious heart or lung diseases, or with serious dysfunction.
  6. Patients who have received local or systemic anti-tumor treatments such as ablation, Transhepatic Arterial Chemotherapy and Embolization (TACE), local radiotherapy of the liver, immunotherapy, targeted therapy, etc., within 4 weeks, or chemotherapy, other trial drugs, or radiotherapy of metastatic lesions within 2 weeks, except for treatment regimens assessed as disease progression according to RECIST v1.1.
  7. Patients with incurable brain metastasis.
  8. All toxicities related to prior locoregional or systemic anti-tumor treatments are still grade 2 or more (except for hair loss and other events that have been judged tolerable by researchers).
  9. Complication histories of liver cirrhosis or HCC such as gastrointestinal hemorrhage, overt hepatic encephalopathy, or refractory ascites within 2 weeks prior to the first dose of study treatment.
  10. Uncontrolled active infection (eg, lung infections, or abdominal infections).
  11. History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival rate > 90%), such as adequately treated early gastric carcinoma, carcinoma in situ of the cervix, non-melanoma skin carcinoma, or localized prostate cancer.
  12. Hepatitis B virus DNA greater than 500 copies/mL, or hepatitis C virus RNA greater than 15 U/mL.
  13. Positive for human immunodeficiency virus (HIV).
  14. Allergic to contrast agents.
  15. Pregnant/lactating women, or women with the possibility of pregnancy.
  16. Any medical conditions which, in the opinion of the investigator, would preclude participation in this clinical trial.