HAIC, Lenvatinib, and Cadonilimab as Conversion Therapy for Initially Unresectable Hepatocellular Carcinoma (CCGLC-011)

A Prospective, Open-label, Single-arm, Phase 2 Study of Hepatic Arterial Infusion Chemotherapy Combined With Lenvatinib and Cadonilimab as Conversion Therapy for Initially Unresectable Hepatocellular Carcinoma

This is an open-label, single-arm, phase 2 study evaluating hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and cadonilimab as conversion therapy for initially unresectable hepatocellular carcinoma (HCC). The primary objective is to assess the conversion rate, defined as the proportion of participants who are deemed amenable to curative-intent treatment by the multidisciplinary team (MDT), including R0 resection, curative ablation, or liver transplantation, after study treatment. Secondary objectives include curative-intent intervention rate, tumor response, survival outcomes, safety, pathological response, and exploratory tissue and blood biomarkers.

Study Overview

• Status: Active, not recruiting
• Conditions: Hepatocellular Carcinoma Non-resectable
• Intervention / Treatment: Procedure: Hepatic arterial infusion chemotherapy (HAIC-FOLFOX); Drug: Lenvatinib; Drug: Cadonilimab

Detailed Description

Hepatocellular carcinoma is frequently diagnosed at an unresectable stage, and effective conversion strategies are needed to increase the chance of subsequent curative-intent treatment. This study is a prospective, open-label, single-arm, phase 2 trial evaluating HAIC-FOLFOX combined with lenvatinib and cadonilimab in participants with initially unresectable HCC.

Eligible participants will receive HAIC-FOLFOX every 3 weeks, lenvatinib orally once daily, and cadonilimab intravenously every 3 weeks. Tumor response and resectability will be evaluated during treatment by a multidisciplinary team (MDT). Curative-intent treatment includes R0 resection, curative ablation, or liver transplantation.

The primary endpoint is conversion rate, defined as the proportion of participants who are deemed amenable to curative-intent treatment by the MDT after study treatment. Secondary endpoints include the curative-intent intervention rate, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), time to response (TTR), duration of response (DoR), safety, pathological complete response (pCR), major pathological response (MPR), and exploratory tissue and blood biomarkers. Participants will be followed for up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Hepatocellular carcinoma proven on biopsy or confirmed by radiological hallmarks according to the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines.
• Age ≥18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

• Not suitable for curative-intent treatment (including radical hepatic resection, liver transplantation, or curative ablation) after evaluation by the hepatobiliary tumor MDT expert group. Specifically, any of the following conditions are met:

  1. R0 resection is not feasible.
  2. In participants without cirrhosis, the volume of normal liver parenchyma is less than 30% of the total liver volume; or in participants with cirrhosis, the volume of normal liver parenchyma is less than 40% of the total liver volume; or ICG-R15 >15%.
  3. BCLC stage B or C.
• No prior systemic anti-tumor treatment for hepatocellular carcinoma before the first dose.
• According to RECIST version 1.1, at least 1 measurable lesion, or a measurable lesion that has clearly progressed after local treatment.

• Participants with portal vein tumor thrombus (PVTT):

  1. Chen's group A and B, or Cheng's type I-III, can be enrolled.
  2. Cheng's type IV, defined as superior mesenteric vein tumor thrombus, cannot be enrolled.

• Participants with hepatic vein tumor thrombus:

  1. VV1 and VV2 can be enrolled.
  2. VV3, or Sakamoto type I (inferior vena cava tumor thrombus), can also be enrolled.
  3. Sakamoto type II (inferior vena cava tumor thrombus extending above the diaphragm) or Sakamoto type III (inferior vena cava tumor thrombus reaching the right atrium) cannot be enrolled.
• Participants with oligometastases outside the liver can be enrolled. Oligometastases are defined as up to three metastatic lesions in a maximum of two organs, with the largest diameter ≤3 cm.
• Child-Pugh score ≤7.

• Adequate organ and bone marrow function within 7 days before enrollment:

  1. Absolute neutrophil count ≥1.5×10^9/L; platelet count ≥75×10^9/L; hemoglobin ≥9.0 g/dL.
  2. Total bilirubin ≤2× upper limit of normal (ULN); ALT and AST ≤5× ULN; serum albumin ≥28 g/L; alkaline phosphatase ≤5× ULN.
  3. Serum creatinine ≤1.5× ULN or creatinine clearance ≥50 mL/min; urine protein <2+; if urine protein ≥2+, 24-hour urinary protein must be <1 g.
  4. INR ≤2.3 or prothrombin time prolongation ≤6 seconds.
• Estimated life expectancy ≥12 weeks.
• Female participants of childbearing potential, or male participants whose partners are of childbearing potential, must agree to use effective contraception during study treatment and for 6 months after the last dose.
• Signed written informed consent and ability to comply with study visits and procedures.

Exclusion Criteria

• Histologically or cytologically confirmed fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma, or mixed histology.
• History of hepatic encephalopathy or liver transplantation.
• Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage. Participants with only minimal radiologic effusion without symptoms may be enrolled.
• Acute or chronic active hepatitis B or C infection, with HBV DNA >2000 IU/mL or 10^4 copies/mL, HCV RNA >10^3 copies/mL, or co-positivity for HBsAg and anti-HCV antibody. Participants controlled to within these limits after antiviral therapy may be enrolled.
• Central nervous system metastases.
• History of esophageal or gastric variceal bleeding due to portal hypertension within 6 months before first dose, or high bleeding risk judged by the investigator.
• Any life-threatening bleeding event within 3 months before first dose.
• History of arterial or venous thromboembolic events within 6 months before first dose, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other serious thromboembolic events, except stabilized catheter-related thrombosis or superficial thrombosis.
• Continuous use of aspirin >325 mg/day or other known platelet inhibitors for 10 days within 2 weeks before first dose.
• Uncontrolled hypertension despite optimal treatment, defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg, or history of hypertensive crisis or hypertensive encephalopathy.
• Toxicities from previous treatment not recovered to grade 0 or 1 per NCI-CTCAE version 5.0, except alopecia or clinically insignificant asymptomatic laboratory abnormalities.
• Symptomatic congestive heart failure (NYHA class II-IV) or left ventricular ejection fraction <50%.
• Symptomatic or poorly controlled arrhythmia, history of congenital long QT syndrome, or screening QTc >500 ms by Fridericia formula.
• Severe bleeding tendency, coagulation disorder, or current thrombolytic therapy.
• Gastrointestinal perforation or fistula, intestinal obstruction, extensive bowel resection with chronic diarrhea, Crohn's disease, ulcerative colitis, or chronic diarrhea within 6 months before first dose.
• Radiotherapy within 3 weeks before first dose, unless all radiation-related toxicities have resolved and there is no need for corticosteroids.
• Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia, severe pulmonary dysfunction, or other severe lung disease.
• Active pulmonary tuberculosis, current anti-tuberculosis treatment, or anti-tuberculosis treatment within 1 year before first dose.
• HIV infection or known syphilis requiring treatment.
• Active or clinically uncontrolled severe infection within 4 weeks before first dose.
• Active autoimmune disease requiring systemic treatment within 2 years before first dose, except replacement therapy.
• Use of immunosuppressive drugs within 4 weeks before first dose, except local or physiologic-dose corticosteroids and temporary corticosteroids for allergy or airway symptoms.
• Live attenuated vaccine within 4 weeks before first dose or planned during the study period.
• Major surgery or unhealed wound, ulcer, or fracture within 4 weeks before first dose.
• Local treatment for hepatocellular carcinoma within 4 weeks before first dose. Traditional Chinese medicine with anti-tumor indications, or immunomodulatory drugs such as thymosin, interferon, or interleukin, within 2 weeks before first dose.
• Other acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that, in the investigator's judgment, increase risk or interfere with study interpretation.
• Other malignancy diagnosed within 5 years before first dose, except radically treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.
• Prior treatment with anti-PD-1, anti-PD-L1/L2, anti-CTLA-4, or other immunotherapy, or prior targeted therapy against VEGF/VEGFR, RAF, MEK, PDGFR, FGFR, or related pathways.
• Known allergy to oxaliplatin, fluorouracil, leucovorin, lenvatinib, cadonilimab, or severe prior allergic reaction to other monoclonal antibodies.
• Aortic dissection aneurysm, celiac trunk dissection aneurysm, or superior mesenteric artery dissection aneurysm.
• Participation in another clinical trial within 4 weeks before first dose.
• Pregnancy or breastfeeding.
• Systemic multiple metastases, portal vein tumor thrombus involving the superior mesenteric vein, or inferior vena cava tumor thrombus extending above the diaphragm or reaching the right atrium.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: HAIC + lenvatinib + cadonilimab; Participants with initially unresectable hepatocellular carcinoma who are evaluated as unsuitable for curative-intent treatment at baseline and receive combined HAIC-FOLFOX, lenvatinib, and cadonilimab as conversion therapy.

Procedure: Hepatic arterial infusion chemotherapy (HAIC-FOLFOX); Administration of oxaliplatin, leucovorin, and fluorouracil via the tumor-feeding hepatic artery every 3 weeks.; Other Names: hepatic arterial infusion chemotherapy of FOLFOX; Drug: Lenvatinib; Lenvatinib administered orally once daily at 8 mg for participants weighing ≤60 kg or 12 mg for participants weighing >60 kg.; Drug: Cadonilimab; Cadonilimab administered intravenously at 10 mg/kg every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion rate	Proportion of participants who are deemed amenable to curative-intent treatment by the multidisciplinary team (MDT), including R0 resection, curative ablation, or liver transplantation, after study treatment. Conversion success will be confirmed only when MDT-defined amenability to curative-intent treatment is maintained for at least 2 months, unless curative-intent treatment is actually performed earlier.	From the date of first treatment to confirmed MDT assessment of amenability to curative-intent treatment, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Curative-intent intervention rate	Proportion of participants who actually undergo curative-intent treatment, including R0 resection, curative ablation, or liver transplantation, after study treatment.	From the date of first treatment to receipt of curative-intent treatment, assessed up to 2 years
Overall response rate (ORR) by mRECIST	Proportion of participants with a best overall response of complete response (CR) or partial response (PR) according to mRECIST during study treatment and follow-up.	Best overall response from the date of first treatment until radiographic disease progression, start of new anti-cancer therapy, death, withdrawal, or end of study, assessed up to 2 years
Overall response rate (ORR) by RECIST 1.1	Proportion of participants with a best overall response of complete response (CR) or partial response (PR) according to RECIST version 1.1 during study treatment and follow-up.	Best overall response from the date of first treatment until radiographic disease progression, start of new anti-cancer therapy, death, withdrawal, or end of study, assessed up to 2 years
Disease control rate (DCR) by mRECIST	Proportion of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to mRECIST during study treatment and follow-up.	Best overall response from the date of first treatment until radiographic disease progression, start of new anti-cancer therapy, death, withdrawal, or end of study, assessed up to 2 years
Disease control rate (DCR) by RECIST 1.1	Proportion of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) according to RECIST version 1.1 during study treatment and follow-up.	Best overall response from the date of first treatment until radiographic disease progression, start of new anti-cancer therapy, death, withdrawal, or end of study, assessed up to 2 years
Overall survival (OS)	OS is measured from the date of first treatment to the date of death from any cause. Participants alive or lost to follow-up will be censored at the date they were last known to be alive.	From the date of first treatment to the date of death from any cause, assessed up to 2 years
Progression-free survival (PFS) by mRECIST	PFS is measured from the date of first treatment to radiographically documented disease progression according to mRECIST or death from any cause, whichever occurs first. Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.	From the date of first treatment to radiographically documented progression according to mRECIST or death from any cause, whichever occurs first, assessed up to 2 years
Time to progression (TTP) by mRECIST	TTP is measured from the date of first treatment to radiographically documented disease progression according to mRECIST. Death from any cause without prior radiographic progression will not be counted as an event.	From the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 2 years
Time to response (TTR) by mRECIST	Time to response (TTR) is defined, among participants who achieve an objective response, as the time from the date of first treatment to the date of first documented complete response (CR) or partial response (PR) according to mRECIST.	From the date of first treatment to the date of first documented CR or PR according to mRECIST, assessed up to 2 years
Duration of response (DoR) by mRECIST	DoR is defined for responders only and is measured from the date of first documented complete response (CR) or partial response (PR) according to mRECIST to the date of first documented disease progression according to mRECIST or death from any cause, whichever occurs first.	From the date of first documented CR or PR according to mRECIST to first documented progression or death from any cause, assessed up to 2 years
Incidence of treatment-related adverse events (TRAEs)	Incidence, nature, and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.	From the date of first treatment to 90 days after last study treatment, assessed up to 2 years and 90 days
Pathological complete response (pCR)	pCR is defined as no residual viable tumor cells in resected or explanted tumor specimens. This outcome will be assessed only in participants with evaluable pathological specimens obtained at curative-intent surgery or liver transplantation.	At the time of curative-intent resection or liver transplantation, assessed up to 2 years
Major pathological response (MPR)	MPR is defined as residual viable tumor cells ≤10% in resected or explanted tumor specimens. This outcome will be assessed only in participants with evaluable pathological specimens obtained at curative-intent surgery or liver transplantation.	At the time of curative-intent resection or liver transplantation, assessed up to 2 years
Exploratory tissue and blood biomarkers associated with treatment response	Exploratory analysis of baseline and on-treatment tissue and blood biomarkers associated with conversion success, treatment response, and survival outcomes.	Baseline, at confirmed conversion success if applicable, at curative-intent surgery if applicable, and at disease progression, assessed up to 2 years

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: Akesobio
• Investigators: Study Chair: Ze-yang Ding, Prof., Tongji Hospital; Study Director: Han Dr. Gao, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: December 8, 2023
• First Submitted That Met QC Criteria: December 17, 2023
• First Posted (Actual): January 3, 2024

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; Lenvatinib; Hepatic Arterial Infusion Chemotherapy; Downstaging conversion therapy; Cadonilimab
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; lenvatinib
• Other Study ID Numbers: 2023-S039

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No