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
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- TaiRx, Inc.
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Objective response rate (ORR)
Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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).
Arms & Interventions
CVM-1118 + Sintilimab + TACE
CVM-1118 (200 mg, PO, BID) + Sintilimab (200 mg, IV, Q3W) + TACE (4 times in maximum)
Intervention: CVM-1118 + Sintilimab + TACE (Combination Product)
Outcomes
Primary Outcomes
Objective response rate (ORR)
Time Frame: Up to approximately 2 years
Objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Secondary Outcomes
- Objective Response Rate (ORR)_mRECIST(Up to approximately 2 years)
- Disease control rate (DCR)(Up to approximately 2 years)
- Duration of response (DoR)(Up to approximately 2 years)
- Progression free survival (PFS)(Up to approximately 2 years)
- Time to progression (TTP)(Up to approximately 2 years)
- Overall survival (OS)(Up to approximately 4 years)
- Rate of Adverse event (AE) and Serious Adverse Event (SAE)(Starting from the first dose of combination treatment until 28 days following the last dose of treatment by CTCAE v6.)
- Maximum Plasma Concentration [Cmax] of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))
- Area Under the Curve [AUC] of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))
- Peak time(Tmax) of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))
- Half time(t1/2) of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))
- Clearance rate(CL) of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))
- Apparent volume of distribution(Vd) of CVM-1118 and its metabolite CVM-1125 after CVM-1118 dosing(During Cycle 1 (each cycle is 21 days))