A Phase IIa, Single-arm, Open-label Clinical Study to Evaluate the Efficacy, Safety and PK of CVM-1118 in Combination With Sintilimab and TACE in Participants With Incurable/Non-metastatic HCC

A Phase IIa, Single-arm, Open-label Clinical Study to Evaluate the Efficacy, Safety and Pharmacokinetic (PK) of CVM-1118 in Combination With Sintilimab and Transarterial Chemoembolization (TACE) in Participants With Incurable/Non-metastatic Hepatocellular Carcinoma

This is a single-arm, open-label Phase IIa study designed to evaluate the efficacy, safety, and PK of CVM-1118 in combination with Sintilimab (Tyvyt ®) and TACE in participants with incurable/non-metastatic HCC.

Approximately 40 participants will be enrolled, all receiving CVM-1118 (200 mg orally [PO], twice daily [BID]) in combination with Sintilimab (200 mg via intravenous [IV] infusion every 3 weeks [Q3W]) and TACE. All participants will initiate treatment with CVM-1118 and Sintilimab on Cycle 1 Day 1 (C1D1), with each cycle lasting 21 days, continuing until the occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, for 2 years (i.e., Cycle 34) or study termination (whichever occurs first). CVM-1118 will be temporarily suspended from 2 days prior to each TACE procedure until 7 days post-TACE. The protocol permits conventional TACE (cTACE) or drug-eluting beads TACE (DEB-TACE) based on investigator's discretion, with the requirement that each participant maintains the same TACE modality throughout the treatment period. The first TACE procedure will be initiated between weeks 2-4 (C1D15 - C2D8) following systemic therapy initiation, with a maximum of 2 TACE treatments per lesion, an interval of ≥1 month between TACE sessions, and no more than 4 TACE treatments in total per participant.

The study comprises four periods: screening, treatment, safety follow-up, and survival follow-up. During the screening period, participants will undergo required examinations and evaluations. Eligible participants will enter the treatment period to receive the combination regimen. Tumor response will be assessed per RECIST v1.1 and mRECIST (see Appendix 1), with evaluations conducted every 9 weeks (±1 week) following initial dosing. During the safety follow-up period, all participants will undergo final safety assessments 28 days (+7 days) after investigational product cessation or prior to initiating new antitumor therapy. Subsequently, participants will enter the survival follow-up period with 12-week interval contacts to document disease status, anti-tumor therapies received, survival status, and other relevant clinical information until death, loss to follow-up, consent withdrawal, or study closure (whichever occurs first).

Throughout the study, participants will undergo scheduled safety evaluations and PK blood sampling at designated timepoints. Subsequent PK sampling schedules may be adjusted or eliminated based on accumulated pharmacokinetic data from preceding participants.

• CVM 1118 will be administered at 200 mg, PO, BID. Treatment continues until unacceptable toxicity, disease progression, death, consent withdrawal, for 2 years (i.e., Cycle 34), or study termination (whichever occurs first). CVM-1118 will be temporarily suspended from 2 days prior to each TACE procedure until 7 days post-TACE. CVM-1118 should be swallowed whole with a glass of water in a fasted state, with no food intake for at least 2 hours before and 1 hour after CVM 1118 administration. CVM 1118 should be administered at approximately the same time each day. Investigators are permitted to adjust the dosing for participants as required by referring to the "Dose Adjustment".
• Sintilimab will be administered at 200 mg, IV, Q3W. Treatment continues until unacceptable toxicity, disease progression, death, consent withdrawal, for 2 years (i.e., Cycle 34) or study termination (whichever occurs first). Investigators are permitted to adjust the drug administration regimen for participants as required by referring to the "Dose Adjustment".
• TACE modality for each participant, including the choice between cTACE and DEB-TACE, will be determined by investigators at their discretion; however, each participant must remain consistent with the selected TACE modality (cTACE or DEB-TACE) throughout the treatment period. The first TACE procedure will be initiated 2-4 weeks after the start of systemic therapy (C1D15 to C2D8), with a maximum of 2 treatments per lesion (minimum 1-month interval between TACE sessions) and up to 4 treatments per participant in total.

This study is conducted in China and is not under a U.S. IND. However, the investigational product is a U.S. FDA-regulated drug with existing INDs [125830, 138523, 138900], and the data from this study are intended to support a future U.S. marketing application.

Inclusion Criteria:

• 1) Participant is ≥18 years of age, at the time of providing the documented informed consent.

  2) Diagnosis of hepatocellular carcinoma

  • Pathologically or cytologically-confirmed or clinically diagnosed in accordance with American Association for the Study of Liver Diseases (AASLD) criteria (i.e., radiologic imaging with cross-sectional multiphasic contrast computed tomography [CT] or magnetic resonance imaging [MRI] showing a ≥ 1 cm liver lesion).

    3) No evidence of extrahepatic disease on any available imaging. 4) Disease not amenable to curative surgery or transplantation or curative ablation.

    5) Disease must be amenable to TACE and anticipated to require no more than 4 TACE treatments for local disease sites, with a maximum of 2 TACE treatments per individual lesion .

    6) Child-Pugh liver function class A (see Appendix 2). 7) At least one measurable (per RECIST 1.1) lesion (see Appendix 1). 8) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (see Appendix 3).

    9) Patients with hepatitis B virus (HBV) infection, defined as hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBcAb) positive, and HBV DNA detected positive (≥10 IU/ml or above the local laboratory's standard detection limit), who have stable disease or show antiviral response (e.g., reduction in HBV DNA levels) after treatment, and agree to receive treatment during the trial, shall be allowed to enroll.

    10) Patients with hepatitis C virus (HCV) infection who agree to receive treatment during the trial are eligible for enrollment.

    11) Participants must have adequate organ and bone marrow function, meeting the following laboratory criteria:

  • Hematology: Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L; Platelet count (PLT) ≥75 × 10⁹/L; Hemoglobin (HGB) ≥9.0 g/dL without transfusion or erythropoietin (EPO) dependency

  • Liver Function: Total bilirubin (T-Bil) ≤2 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN; Serum albumin ≥30 g/L

  • Renal Function: Non-indexed eGFR ≥ 60 mL/min (formula in Appendix 4)

  • Coagulation: International normalized ratio (INR) ≤2 × ULN; prothrombin time (PT) ≤1.5 × ULN 12) Life expectancy of ≥12 weeks. 13) Male and female participants of childbearing potential must agree to use effective contraception from the signing of the informed consent form (ICF) until 6 months after the last dose of the investigational product. Female participants of childbearing potential are defined as premenopausal women. A negative pregnancy test result must be confirmed for all female of childbearing potential within ≤7 days prior to the first dose of the investigational product.

    14) Signed written informed consent form and ability to comply with protocol-specified visits and related procedures.

Exclusion Criteria:

• 1) Known hypersensitivity to CVM-1118, Sintilimab components, or severe allergic reactions to monoclonal antibodies.

  2) Histologically/cytologically confirmed components of fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma, etc.

  3) Has HCC lesions occupying ≥50% of the liver volume. 4) Major portal vein tumor thrombosis involving the main trunk and its first-order branches (i.e., Vp3 and Vp4), as demonstrated by imaging performed during the screening period.

  5) Is currently a candidate for liver transplantation. 6) Receipt of anti- programmed cell death protein 1 (PD-1), anti- programmed death - ligand 1 (PD-L1), or anti - programmed death - ligand 2 (PD-L2) agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., Cytotoxic T - lymphocyte - associated protein 4 [CTLA-4]).

  7) Receipt of locoregional therapy to existing liver lesions (such as TACE, transcatheter arterial embolization [TAE], transarterial radioembolization (TARE), hepatic arterial infusion, or radiation,) for treatment of HCC. Use of TACE or TAE as part of a curative therapy (e.g., in conjunction with ablation or surgery) can be acceptable if it is used in the lesions where curative therapy was attempted. However, TACE or TAE cannot have been used as sole modalities in prior curative therapy.

  8) Receipt of prior systemic anticancer therapies for HCC. 9) History of abdominal fistula or gastrointestinal (GI) perforation, non-healed gastric ulcer that is refractory to treatment, or active GI bleeding within 6 months prior to enrollment.

  10) Has bleeding or thrombotic disorders or is using anticoagulants requiring therapeutic INR monitoring, e.g., warfarin or similar agents. Treatment with antiplatelet agents and low molecular weight heparin is permitted.

  11) Has clinically apparent ascites on physical examination that is not controlled with medication.

Note: Ascites detectable on imaging studies only are allowed 12) Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to therapy. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are excluded.

13) Has medical contraindications that preclude all forms of contrast enhanced imaging (CT or MRI).

14) Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of CVM-1118.

15) Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.

16) Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of investigational product.

17) Has significant cardiovascular impairment within 12 months of the first dose of investigational product such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II (Appendix 5), unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability.

18) Has had major surgery to the liver within 4 weeks prior to the first dose of investigational product.

Note: If participant underwent major surgery, they must have adequately recovered from the toxicity and/or complications from the intervention prior to starting investigational product.

19) Has had a minor surgery within 7 days prior to the first dose of investigational product.

20) Has serious nonhealing wound, ulcer, or bone fracture. 21) Has received a live vaccine within 30 days prior to the first dose of investigational product.

22) Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of investigational product.

Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or 5 half-lives (whichever is longer) after the last dose of the previous investigational agent.

23) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of investigational product.

24) Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy [e.g., ≤10 mg prednisone] for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.

25) Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

26) Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

27) Patients with co-existing active HBV and HCV infections. 28) Has an active infection including tuberculosis or human immunodeficiency virus (positive HIV antibodies).

29) Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 hours will be ineligible.

30) Has had an allogenic tissue/solid organ transplant. 31) Other conditions that, in the investigator's judgment, would increase study risk, interfere with results, or render the participant ineligible.