This trial is a single-arm, open-label, exploratory first-in-human clinical study designed to evaluate the safety and tolerability of HNF4α srRNA injection in patients with locally unresectable or metastatic colorectal cancer, and to preliminarily explore its effectiveness in treating metastatic colorectal cancer.
Males or females, aged 18 years or older.
Patients with histologically confirmed colorectal cancer that has been determined to be unresectable or metastatic.
Colorectal cancer subjects who are unsuitable or unable to tolerate standard systemic therapy, or who have received standard systemic therapy but have disease progression based on RECIST (version 1.1) criteria, including chemotherapy based on fluorouracil, oxaliplatin, or irinotecan, and targeted therapies with anti-VEGF/EGFR monoclonal antibodies.
Patients with confirmed deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) in tumor tissue, who have been treated with immune checkpoint inhibitors (anti-PD-1 or anti-PD-L1 antibodies) and are assessed with disease progression.
Patients with any of the following criteria were excluded from participation in this study
Patients who have undergone standard adjuvant chemotherapy after tumor resection, and have experienced recurrence or metastasis within 6 months after discontinuing the medication, and have not received standard systemic therapy.
Clinical or imaging indications suggest the current presence of intestinal obstruction, perforation, or bleeding; or those who, upon investigator assessment, are at a higher risk of perforation or bleeding.
Inadequate liver function：serum bilirubin > 3 × the upper limit of normal (ULN), or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or alanine aminotransferase (ALT) > 5 × ULN.
Single group
HNF4α srRNA
DrugHNF4α srRNA will be administered intravenously for the treatment of metastatic colorectal cancer. 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, after enrollment, the investigator will determine the HNF4α srRNA dose, whether to combine it with immunotherapy, and the dose and schedule of the combination, based on the patient's treatment history and the safety/efficacy data of HNF4α srRNA administered via peripheral vein for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal cancer. Participants initially on HNF4α srRNA monotherapy who are considered for combination with immunotherapy must complete at least two treatment cycles and the post - treatment safety assessment.
To evaluate the tolerability and safety for intravenous HNF4α srRNA in subjects with metastatic colorectal cancer
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 also 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 CRC tissue through next-generation sequencing
The impact of HNF4α srRNA treatment on cytokines in serum
The detection of cytokines in patient serum before and after treatment of HNF4α srRNA
The impact of HNF4α srRNA treatment on immune cell subsets in serum or tissuses
The detection of immune cell subsets in patient serum or tissues before and after treatment of HNF4α srRNA
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