A Clinical Trial for the Safety and Efficacy of CD-801 in Patients With Advanced Hepatocellular Carcinoma

The goal of this investigator-initiated, a single-arm, open-label, pilot study is to investigate the safety, tolerability, and efficacy of CD-801 treatment in subjects with advanced hepatocellular carcinoma.

Condition of disease: advanced hepatocellular carcinoma .

Intervention：treatment with 100μg CD-801 through the hepatic artery at two-week intervals. The dosing interval will be adjusted based on subject tolerability, safety, and efficacy. For example, it may be adjusted to administer the medication once every three weeks or four weeks.

Drug: CD-801, a drug designed specifically to enhance the expression of HNF4α and selectively target liver cancer cells.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Recent advancements in understanding tumor biology and the tumor microenvironment have dramatically transformed the treatment landscape for advanced stage HCC. However, the survival for advanced HCC patients still remains unsatisfactory.

Differentiation therapy in oncology is defined as a therapeutic strategy that reactivates endogenous differentiation programs and reverts malignant phenotypes. Its hallmark success is the treatment of acute promyelocytic leukemia (APL) by the combination of all-trans retinoic acid (ATRA) and arsenic. Unfortunately, this approach has achieved limited success in solid tumors.

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor (TF) belonging to the nuclear receptor family. HNF4α is highly enriched in mature hepatocytes and serves as a master regulator of hepatocyte differentiation and hepatic metabolism. Previous studies, including the investigators' and others, have demonstrated that the reduced expression of HNF4α plays a critical role in hepatocarcinogenesis. Restoring HNF4α expression induces the differentiation of HCC cells into mature hepatocytes and has shown significant therapeutic effects in various animal models of HCC.

In this study, the investigators developed CD-801, a drug designed specifically to enhance the expression of HNF4α and selectively target liver cancer cells, for the treatment of HCC patients. Preclinical studies have shown that CD-801 effectively inhibits the growth of subcutaneous and orthotopic liver tumors in mice. Acute toxicity tests in SD rats have demonstrated that a single intravenous injection of CD-801 injection at a dose of 150 μg/animal is well-tolerated, with no significant toxicity, indicating good safety profiles. Furthermore, in the dose escalation phase of the clinical trial which the investigators have completed, CD-801(25, 50 and 100 μg) was found to be well-tolerated. None of the patients experienced dose-limiting toxicities (DLTs) during the DLT phase.

This trial is a single-arm, open-label, exploratory clinical study aimed at further evaluating the efficacy, safety, and tolerability of 100 μg CD-801 administered through the hepatic artery in the treatment of advanced-stage HCC at two-week intervals (The dosing interval will be adjusted based on subject tolerability, safety, and efficacy. For example, it may be adjusted to administer the medication once every three weeks or four weeks).

Eligibility Criteria:
Inclusion Criteria:

1. Males or females, aged 18 years or older.
2. Subjects must have confirmed diagnosis of HCC according to the American Association for the Study of Liver Diseases criteria.
3. Unresectable HCC.
4. Subjects are unsuitable for local or systemic anti-tumor therapy or had tumor progression after receiving at least one kind of conventional treatment.
5. According to mRECIST, subjects should be with at least 1 measurable target lesion.
6. Life expectancy of 12 weeks or more.
7. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2.
8. Male 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.
9. Subjects who have voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

Exclusion Criteria:

1. ALB \< 28 g/L, or Bilirubin \>5.0 mg/dL, or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or alanine aminotransferase (ALT) \>5×ULN.
2. Inadequate renal function defined as creatinine \>1.5 times the upper limit of normal (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. Subjects with a history of liver transplantation.
6. Subjects with poorly controlled hypertension, diabetes or other serious heart or lung diseases, or with serious dysfunction.
7. Subjects with extrahepatic metastasis who had potential benefit from first-line systemic therapies.
8. Subjects who had prior anticancer treatment with any locoregional therapies, antiangiogenic targeted therapies, immune checkpoint inhibitors or chemotherapy within 4 weeks (within 2 weeks in case of sorafenib), radiotherapy within 3 weeks, or active traditional Chinese medicine within 2 weeks before the first dose of study treatment, except for the treatments after which the disease still progressed according to mRECIST.
9. 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).
10. Subjects with complication histories of liver cirrhosis or HCC such as gastrointestinal hemorrhage, overt hepatic encephalopathy, or uncontrollable ascites within 2 weeks prior to the first dose of study treatment.
11. Uncontrolled active infection (eg, lung infections, or abdominal infections).
12. Subjects with moderate to severe hepatic artery- portal vein fistula or hepatic artery - vein fistula which could not be avoided even through the artery super selection by DSA.
13. 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 OS rate \> 90%), such as adequately treated early gastric carcinoma, carcinoma in situ of the cervix, non-melanoma skin carcinoma, or localized prostate cancer.
14. HBV DNA greater than 500 copies/mL, or HCV RNA greater than 15 U/mL.
15. Subject is positive for Human Immunodeficiency Virus (HIV).
16. Any subject who is allergic to MRI contrast agents.
17. Pregnant/lactating women, or women who have the possibility of pregnancy.
18. Participation in other investigational drug trials within 4 weeks prior to initiation of this study treatment.
19. Any medical or other condition which, in the opinion of the investigator, would preclude participation in this clinical trial.