Hepatocellular Carcinoma

Primary Objective: By comparing MTL-CEBPA with sorafenib versus sorafenib monotherapy, as directed by BICR according to RECIST v1.1 guidelines, to determine progression-free survival (PFS). Secondary Objectives: - By comparing MTL-CEBPA with sorafenib versus sorafenib monotherapy, BICR will assess the following: best objective response (BOR), objective response rate (ORR), duration of response (DoR), time to response (TTR), and change in tumor size. - Compare overall survival (OS) of MTL-CEBPA with sorafenib versus sorafenib monotherapy. - Assess the concordance between BICR and trial administrators on tumor efficacy assessment indicators. - Assess the safety and tolerability profile of MTL-CEBPA with sorafenib versus sorafenib monotherapy. - Assess health-related quality of life (HRQoL) using the EORTC-QLQ-C30 plus EORTC-QLQ-HCC18 QOL questionnaire, comparing MTL-CEBPA with sorafenib versus sorafenib monotherapy. Exploratory Purposes - Assess efficacy by comparing MTL-CEBPA with sorafenib versus sorafenib monotherapy, according to the revised (m) RECIST. - Future Biological Studies (Optional) - Identify molecular (genomic, metabolic, and/or proteosome) biomarkers that may predict or establish clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanisms of action of MTL-CEBPA and sorafenib in all participants. These may include, but are not limited to, tumor mutational burden (TMB), circulating tumor DNA, somatic mutations, circulating mutant proteins/cytoplasmic regeneration, lymphocyte and bone marrow cell counts.

液劑
錠劑

MTL-CEBPA
Nexavar

084
110

50mg/20mL
200mg/ tablet

PFS was evaluated by BICR according to RECIST v1.1.

1. Obtain written informed consent before any specific trial-related procedures.

2. Male or female aged 18 years or older.

3. Participants with a history of hepatitis B and/or C, and histologically confirmed advanced HCC with cirrhosis. Participants with a past or current hepatitis C virus (HCV) infection are eligible to participate in the trial. Participants must have completed at least one month of treatment and have an HCV viral load below the quantification limit before starting the trial intervention. Participants who are HCV antibody (Ab) positive but HCV RNA negative due to previous treatment or spontaneous resolution are eligible. Participants with a past history of hepatitis B or currently controlled hepatitis B are eligible, provided their hepatitis B virus (HBV) viral load is below 500 IU/mL before receiving the first dose of the investigational drug. Participants currently receiving HBV treatment with a viral load below 100 IU/mL should maintain the same treatment throughout the trial intervention.

4. Child-Pugh Class A.

5. Unsuitable for liver tumor resection and/or local regional therapy.

6. Unqualified for liver transplantation.

7. HCC progression or recurrence following prior treatment with atezolizumab and bevacizumab. Participants who have experienced HCC progression or recurrence while receiving concomitant therapy with a non-atezolizumab anti-PD-1/PD-L1 inhibitor and a non-bevacizumab anti-VEGF agent, or any of these as monotherapy, and who have not previously received atezolizumab and bevacizumab, are eligible.

8. No prior use of tyrosine kinase inhibitors, including sorafenib, regorafenib, cabozantinib, and lenvantinib.

9. BCLC Class C participants. Participants in BCLC Class B (Appendix B) are permitted if unsuitable for local regional therapy or unresponsive to local therapy, and unsuitable for curative therapy. 10. East Coast Cancer Clinical Research Consortium (ECOG) performance status of 0 or 1.

11. Ability to swallow and retain oral medications.

12. Life expectancy greater than 3 months at the time of recruitment.

13. Measurable liver lesions assessed by at least one trial principal investigator (RECIST v1.1).

14. Platelet count > 70 x 10⁹/L.

15. Serum albumin ≥ 28 g/L.

16. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 x Upper Limit of Normal (ULN).

17. Bilirubin ≤ 50 μmol/L.

18. White blood cell (WBC) ≥ 2.0 x 10⁹/L.

19. Absolute neutrophil count ≥ 1.5 x 10⁹/L.

20. Hemoglobin ≥ 9.0 g/dL.

21. International Normalized Ratio (INR) < 1.5.

22. Calculated creatinine clearance ≥ 50 mL/min (Cockcroft & Gault formula).

23. Adverse events from previous treatments must have been resolved to a grade ≤1 (except for hair loss or endocrine disorders adequately controlled by hormone replacement therapy).

24. Women of fertility with a negative blood pregnancy test (within 10 days prior to the first administration of the investigational drug). 25. Women of childbearing potential must agree to use a highly effective* method of contraception, as recommended in the sorafenib US package insert, throughout the entire trial treatment with MTL-CEBPA and sorafenib, and additionally for at least six months after the last dose of MTL-CEBPA and at least six months after the last dose of sorafenib. Women of childbearing potential using hormonal contraception are advised to use an additional second (barrier) method of contraception.

*A highly effective method of contraception is defined as one that, when used correctly and consistently (e.g., inserts, injections, oral contraceptives, some intrauterine devices, bilateral tubal closure, abstinence consistent with the participant's preferred and habitual lifestyle, or a partner who has undergone vasectomy), has a low failure rate (i.e., less than 1% per year).

26. If the male participant's partner is fertile, the male participant must use highly effective contraception during treatment and for at least three months after the last dose of MTL-CEBPA, and must use barrier contraception plus an additional method of contraception to achieve an annual failure rate of <1%. Male participants will also be advised to abstain from intercourse with pregnant or breastfeeding women, or to use condoms.

If the male participant's partner is fertile, the male participant must use highly effective contraception during sorafenib treatment and for three months after the last dose of sorafenib, following the recommendations in the sorafenib USPI.

27. Abstinence is acceptable only if it is a preferred and habitual lifestyle for the participant. Regular abstinence (i.e., using calendar, ovulation, symptom, post-ovulation methods), abstinence declared during IMP exposure, and withdrawal with interrupted intercourse are not acceptable methods of contraception.

28. Compliance with all provisions of the trial protocol.

1. Child-Pugh classification B and C.

2. Participants with no history of hepatitis B and/or hepatitis C.

3. Participants with fibrous lamellar and mixed hepatocellular/cholangiocarcinoma subtype HCC.

4. Participants who have not received prior therapy and are eligible for first-line treatment with atezolizumab and bevacizumab.

5. Participants who received the investigational drug within 30 days prior to the start of the trial.

6. Participants with clinically significant ascites.

7. Participants who have experienced any esophageal variceal bleeding or other uncontrolled bleeding events, including clinically significant epistaxis, within 3 months prior to the start of the trial.

8. Participants with a clinically diagnosed hepatic encephalopathy who have not responded to treatment in the past 6 months.

9. Participants with a history of bleeding or gastrointestinal bleeding or perforation.

10. Active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated metastases are eligible to participate, provided they have undergone repeat imaging during the trial screening period, their radiological findings show stability for at least 4 weeks, stable clinical condition, and no need for steroid treatment for at least 28 days prior to the first dose of the experimental treatment. All participants with stable brain metastases at screening will undergo an MRI brain scan (CT scan will be permitted if there are contraindications to MRI).

11. Participants who received serum albumin within 7 days prior to the first dose of the experimental treatment.

12. Known HIV infection with a CD4+ T cell count <350 cells/μL, or a history of opportunistic infection that could define Acquired Immunodeficiency Syndrome (AIDS). HIV testing is not required unless mandated by local health authorities.

13. Received a live vaccine within 30 days prior to the first dose of the experimental treatment. Live vaccines include, but are not limited to: measles, mumps, rubella, varicella/shingles (chicken pox), yellow fever, rabies, BCG, and typhoid vaccines. Seasonal influenza vaccines are usually inactivated virus vaccines and are permitted; however, intranasal influenza vaccines (e.g., FluMist®) are inactivated live vaccines and are not permitted.

14. Participants with other malignancies within the five years prior to screening, whose malignancies have worsened or require aggressive treatment, but for which the risk of metastasis or death is negligible (e.g., treatment intended to cure early-stage cancer, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical cancer in situ, or breast cancer in situ that has received potentially curative treatment).

15. Participants exhibiting a significantly prolonged QT/QTc interval at baseline, defined as repeatedly showing a QTc interval ≥ 450 ms (male) and ≥ 460 ms (female) using the Fridericia correction formula.

16. Participants with a diastolic blood pressure > 90 mmHg at screening.

17. Participants who develop clinically significant cardiovascular disease within 12 months of the first dose of the trial intervention, including New York Heart Association grade III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or arrhythmia related to hemodynamic instability.

Note: Medically controlled arrhythmias are permitted.

18. Participants who have undergone major surgery within 30 days prior to the start of the trial intervention. If a participant has undergone major surgery, they must have fully recovered from the surgery and/or any surgical complications before starting the trial intervention.

19. Participants with a history of organ transplantation.

20. Participants diagnosed with immunodeficiency or receiving chronic systemic steroid therapy (more than 10 mg prednisone equivalent daily) or any other form of immunosuppressive therapy.

21. Participants who develop sepsis, ineffective bile drainage with or without cholangitis, obstructive jaundice, or encephalopathy within two weeks prior to screening return or the start of the trial treatment.

22. Participants with evidence of spontaneous bacterial peritonitis, renal failure, or allergic reactions within two weeks prior to screening return or the start of the trial treatment (whichever is earlier).

23. Pregnant or breastfeeding women.

24. Known allergy to the active substance (MTL-CEBPA) or any excipient.

25. A history or evidence of any other condition or treatment, including mental or substance abuse disorders, which the trial administrator determines may affect trial administration or confound results, pose a risk to the participant, render participation not in their best interest, or may affect their ability to comply with the trial protocol-specific procedures during the trial.