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A Phase II Study of Cadonilimab Plus Lenvatinib Versus Lenvatinib in Advanced Hepatocellular Carcinoma After Atezolizumab/Bevacizumab Progression

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What is this trial about?

A plain-language summary of the goals, design and what participants do

Hepatocellular Carcinoma is a common type of liver cancer that can spread and become difficult to treat. Some patients have already received medicines called atezolizumab and bevacizumab, but the cancer continued to grow.

The study looks at two treatment options. One group receives a combination of an intravenous medicine named AK104 and an oral pill called Lenvatinib. AK104 is a laboratory‑made protein that helps the body’s immune system recognize and attack cancer cells. Lenvatinib is a tablet that blocks signals that tumors use to grow and form new blood vessels. The other group receives only Lenvatinib tablets.

The purpose of the study is to compare how well the combination therapy works versus the single drug in shrinking tumors. Participants are assigned at random to one of the two groups and will take the assigned medication for several months, with regular doctor visits, blood tests, and imaging scans to watch the cancer’s response and check for side effects.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Randomization
After joining the study you are assigned by the study system to one of two groups: the combination group that receives both cadonilimab and lenvatinib, or the lenvatinib‑only group.
Step 2
Start oral medication
You begin taking lenvatinib in the form of hard capsules that contain 12 mg of the drug.
The capsules are taken by mouth as directed by the study protocol.
Step 3
Intravenous infusion (combination arm only)
If you are in the combination group you receive an intravenous infusion of cadonilimab at a dose of 6 mg per kilogram of body weight.
The infusion is administered by qualified staff in the clinic according to the study schedule.
Step 4
Routine safety monitoring
Regular clinic visits are scheduled to check vital signs, perform an electrocardiogram (ecg), and collect blood for laboratory tests.
Any side effects or adverse events are recorded and evaluated at each visit.
Step 5
Tumor imaging assessments
Imaging studies are performed at predefined intervals to evaluate tumor response.
The response is measured using the RECIST v1.1 criteria, which compare tumor size over time.
Step 6
Pharmacokinetic and immunogenicity sampling
Blood samples are taken to determine the concentration of cadonilimab in the serum (pharmacokinetic assessment).
Additional samples are analyzed for the presence of antibodies against the drug (immunogenicity assessment).
Step 7
Continuation or discontinuation
Treatment continues until the study ends, disease progression is documented, or side effects become unacceptable.
The decision to stop treatment is made by the study investigators based on the collected safety and efficacy data.

Who can join the trial?

12 criteria

You must voluntarily sign the Informed Consent Form (a document that shows you agree to join the study) before any study procedures are done.
You must be at least 18 years old when you sign the consent form.
You must have a confirmed diagnosis of hepatocellular carcinoma (liver cancer) either by tissue testing (looking at cells under a microscope) or by accepted clinical criteria.
Your liver cancer must be classified as stage B or C according to the Barcelona Clinic Liver Cancer (BCLC) system and not be suitable for surgery that could cure it.
Your disease must have gotten worse after the first‑line treatment with the combination of atezolizumab and bevacizumab (a type of cancer‑fighting medication).
You must have at least one tumor that can be measured on scans, using RECIST v1.1 criteria (a standard way doctors measure tumor size). If a tumor was previously treated locally, it can be used as the target if it shows progression.
Your liver function must be Child‑Pugh Class A (the best category of liver health) measured within 7 days before randomization.
Your overall health and blood test results must show adequate organ and blood (hematologic) function, checked within 7 days before randomization.
Your ability to carry out daily activities must be a score of 0 or 1 on the ECOG performance status scale (0 = fully active, 1 = restricted in physically strenuous activity) measured within 7 days before randomization.
You must be expected to live at least 3 more months.
If you have hepatitis B (HBV) infection (positive for HBsAg or HBV‑DNA), the amount of virus in your blood must be less than 2000 IU/mL and you must agree to take standard antiviral therapy throughout the study.
If you have hepatitis C (HCV) infection (positive for HCV antibodies or HCV‑RNA), the infection must be stable as judged by the doctor, and if you are on antiviral treatment you must continue it during the study.

Who cannot join the trial?

18 criteria

Cannot have the rare liver cancer types called fibrolamellar HCC, sarcomatoid HCC, or a mix of liver cancer with another cancer called cholangiocarcinoma.
Cannot have fluid that builds up and causes symptoms in the chest (pleural effusion), around the heart (pericardial effusion), or in the abdomen (ascites) and needs to be drained repeatedly.
Cannot have had bleeding from enlarged veins in the esophagus or stomach (esophageal or gastric varices) within the past 6 months.
Cannot have side effects from previous cancer treatment that are still more than very mild (higher than grade 1 on a standard toxicity scale).
Cannot have had another cancer (besides liver cancer) in the past 3 years, except for very low‑risk cancers such as fully treated skin cancers (basal or squamous cell), superficial bladder cancer, or early‑stage cancers that rarely spread.
Cannot have an active autoimmune disease that needed strong medicines (like disease‑modifying drugs, steroids, or other immune‑suppressing drugs) in the past 2 years. Regular hormone replacement (thyroxine, insulin, or physiologic steroid replacement) does not count.
Cannot have serious heart or blood‑vessel problems (significant cardiovascular disease).
Cannot have current or past interstitial lung disease (a type of lung scarring) that required steroid treatment.
Cannot have had a deep vein clot (deep vein thrombosis), a lung clot (pulmonary embolism), or any other serious clotting problem in the past 3 months.
Cannot have a strong tendency to bleed, problems with blood clotting, be on clot‑dissolving drugs, or be taking blood thinners that need regular INR monitoring.
Cannot have tumor growing into major veins such as the superior mesenteric vein, the inferior vena cava, or other large veins.
Cannot have cancer that has spread to the brain or spinal cord (central nervous system metastases).
Cannot have received any liver cancer treatment within 3 weeks before the first dose of the study medication.
Cannot have received systemic cancer therapy other than the two specified drugs (atezolizumab and bevacizumab).
Cannot have taken herbal or Chinese medicines that are meant to treat cancer or affect the immune system (including drugs like thymidine, interferon, interleukin) within 2 weeks before the first dose.
Cannot have taken part in another clinical trial within 4 weeks before the first dose, unless it was a non‑interventional study or a follow‑up period of a previous trial.
Cannot have had a liver transplant.
Cannot have had hepatic encephalopathy (confusion caused by severe liver disease).

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

ASST Grande Ospedale Metropolitano Niguarda
Verified
Milan, Italy
Centre Hospitalier Universitaire De Bordeaux
Verified
Bordeaux, France
Istituto Europeo Di Oncologia S.r.l.
Responsive
Milan, Italy

Trial locations

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Investigated drugs

Lenvatinib
is an oral medication taken in capsule form. It works by blocking several signals that cancer cells use to grow and form new blood vessels. In this study, patients with advanced liver cancer take lenvatinib to see how well it can control the disease when used alone or together with another drug.
Cadonilimab
is given by an IV infusion. It is a type of antibody that helps the body’s immune system recognize and attack cancer cells. In the trial, cadonilimab is tested in combination with lenvatinib to see if adding this immune‑targeting therapy improves the response compared with lenvatinib alone.

Lenvatinib

What is already known about the treatment

Lenvatinib
Lenvatinib is taken as a hard capsule taken by mouth. It is an approved medicine that is used for advanced liver cancer and other solid tumors. It works by blocking several proteins called tyrosine kinases (such as VEGFR, FGFR, PDGFR and KIT) that help tumors grow new blood vessels. It belongs to the class of multi‑kinase inhibitors with anti‑angiogenic activity.
Cadonilimab
Cadonilimab is given as an intravenous solution that is infused into a vein. It is currently an investigational drug being studied in clinical trials for liver cancer and other cancers. It is a bispecific antibody that attaches to both PD‑1 and CTLA‑4 proteins on immune cells, stopping these checkpoints and allowing the immune system to attack the tumor. It is classified as a bispecific immune‑checkpoint inhibitor monoclonal antibody.

Investigated diseases

Hepatocellular carcinoma (HCC) - Hepatocellular carcinoma is a cancer that begins in the main cells of the liver. It usually develops in people who have long‑term liver damage such as cirrhosis or chronic viral hepatitis. The tumor can grow within the liver, forming a lump that may increase in size over time. As it expands, cancer cells can invade nearby blood vessels and spread to other parts of the liver. In later stages, the disease may extend beyond the liver to organs such as the lungs or bones.