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.
Males or females, aged 18 years or older.
Histologically or cytologically confirmed intrahepatic cholangiocarcinoma patients.
Patients with intrahepatic cholangiocarcinoma not suitable for surgical resection, liver transplantation, or ablation therapy, or those with post-surgical recurrence and/or metastasis.
Patients not suitable for local or systemic treatment, or those who have progressed after at least one chemotherapy regimen containing gemcitabine/fluoropyrimidine/platinum, etc..
Patients with any of the following criteria were excluded from participation in this study
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.
Inadequate renal function defined as creatinine >1.5 × ULN or calculated creatinine clearance < 40 mL/min.
Absolute neutrophil count (ANC) < 1.0×109/L, or Platelets < 30×109/L, or Hemoglobin < 8.5 g/dL.
Single group
HNF4α srRNA
DrugHNF4α 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. 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.
To evaluate the tolerability and safety for intravenous HNF4α srRNA in subjects with intrahepatic cholangiocarcinoma (ICC)
Safety and tolerability are assessed based on the incidence of Dose-Limiting Toxicities (DLTs) within 14 days post-initial drug administration, along with the frequency and severity of adverse events (AEs), serious adverse events (SAEs), and events leading to treatment discontinuation throughout the treatment period, all evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. According to Amendment 1, the primary endpoint has been amended from assessing the incidence and severity of DLTs, adverse events (AEs), serious adverse events (SAEs), and AEs leading to treatment discontinuation (evaluated per NCI-CTCAE 5.0) with HNF4α srRNA therapy to assessing these outcomes for both HNF4α srRNA monotherapy and combination therapy.
To assess the objective response rate (ORR) by RECIST v1.1
To assess the proportion of subjects who have best overall response of complete response or partial response at the time of data cutoff based on RECIST v1.1. According to Amendment 1, the secondary endpoint has been updated from evaluating the ORR per RECIST v1.1 with HNF4α srRNA therapy to evaluating the ORR for both monotherapy and combination therapy with HNF4α srRNA per RECIST v1.1.
Duration of response based on RECIST v1.1
To assess the time from the first documentation of complete response or partial response to the date of first documentation of disease progression or death (whichever occurs first) based on RECIST v1.1
Progression-free survival based on RECIST v1.1
To assess the time from the first study dose date to the date of first documentation of disease progression or death(whichever occurs first) based on RECIST v1.1
Time to response based on RECIST v1.1
To assess the time from the date of first study dose to the date of first documentation of complete response or partial response based on RECIST v1.1
The assessment of whether the efficacy of HNF4α srRNA is related to specific mutations
Identification of whether the efficacy of HNF4α srRNA is related to specific gene mutations in ICC tissue through next-generation sequencing
The impact of HNF4α srRNA treatment on proteomics in serum
The detection of proteomics in patient serum before and after treatment of HNF4α srRNA
The impact of HNF4α srRNA treatment on metabolomics in serum
The detection of metabolomics in patient serum before and after treatment of HNF4α srRNA
The impact of HNF4α srRNA treatment on cytokines in serum
The detection of cytokines in patient serum before and after treatment of HNF4α srRNA
Click on the lead sponsor to view all of their trials.
