Phase III Randomized Study of Durvalumab, Tremelimumab, and Lenvatinib with TACE versus TACE Alone in Locoregional Hepatocellular Carcinoma

The primary objective of this study is to demonstrate the **superiority** of the combination therapy of durvalumab, tremelimumab, lenvatinib, and transarterial chemoembolization (TACE) compared to TACE alone by assessing progression-free survival (PFS) in participants with locoregional hepatocellular carcinoma (HCC). This is clinically relevant as improving PFS can potentially lead to better management and outcomes for patients with this type of liver cancer.

Secondary objectives include:

• To demonstrate the superiority of durvalumab, tremelimumab, lenvatinib, and TACE relative to TACE alone by assessing overall survival (OS) in participants with locoregional HCC.
• To demonstrate the superiority of durvalumab, tremelimumab, and TACE relative to TACE alone by assessing PFS in participants with locoregional HCC.
• To demonstrate the superiority of durvalumab, tremelimumab, and TACE relative to TACE alone by assessing OS in participants with locoregional HCC.

These secondary objectives aim to further evaluate the potential benefits of the combination therapies in extending survival and improving outcomes for patients with locoregional HCC.

The clinical trial involves a total of **594 participants** diagnosed with **locoregional hepatocellular carcinoma (HCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including the absence of extrahepatic disease and the disease's amenability to transarterial chemoembolization (TACE). The trial includes individuals with a Child-Pugh score class A and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating a relatively stable general health status. The study also considers vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, sponsor-blinded, multicenter study to evaluate the efficacy of **durvalumab** in combination with **tremelimumab** and **lenvatinib**, administered concurrently with transarterial chemoembolization (TACE), compared to TACE alone in patients with locoregional **hepatocellular carcinoma** (HCC). The primary objective is to demonstrate the superiority of the combination therapy in terms of progression-free survival (PFS) as assessed by RECIST 1.1 criteria. Secondary endpoints include overall survival (OS). The trial is expected to commence recruitment on March 11, 2024, and conclude by February 26, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as the absence of extrahepatic disease, non-amenability to curative surgery, and adequate organ function. Following randomization, participants will receive either the combination therapy or TACE alone. Study visits will include regular follow-up assessments to monitor disease progression and treatment response. The end-of-study visit will occur upon completion of the treatment period or in the event of disease progression or unacceptable toxicity.

The expected duration of participant involvement is up to 39 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Durvalumab**, marketed as IMFINZI, which is provided as a 50 mg/mL **concentrate for solution for infusion**. This experimental medication is administered intravenously. The maximum treatment period for Durvalumab is 36 months. The active substance, Durvalumab, is a protein-based therapeutic agent developed by AstraZeneca AB. The administration schedule and dosage are determined by the study protocol, and participant compliance is monitored throughout the trial.

**Tremelimumab**, marketed as IMJUDO, is another experimental medication used in the trial. It is available as a 20 mg/mL concentrate for solution for infusion and is administered intravenously. The treatment period for Tremelimumab is limited to 1 month. Like Durvalumab, Tremelimumab is a protein-based therapeutic agent developed by AstraZeneca AB. The administration and dosing schedule are specified in the study protocol, with compliance monitoring in place.

**Lenvatinib**, marketed as LENVIMA, is provided in the form of 4 mg hard capsules. This experimental medication is administered orally, with a maximum treatment period of 36 months. Lenvatinib is a chemically synthesized active substance developed by Eisai GmbH. The dosing schedule is outlined in the study protocol, and participant adherence is monitored.

In addition to the experimental treatments, the trial includes the use of **Mycophenolate Mofetil** as a non-experimental treatment. It is provided in capsule form and administered orally. Mycophenolate Mofetil serves as an immunosuppressive agent, and its administration is guided by the study protocol. The maximum treatment period for Mycophenolate Mofetil is 39 months, with compliance monitoring implemented.

**Infliximab** is also used as a non-experimental treatment in the trial. It is available as a powder for concentrate for solution for infusion and is administered intravenously. Infliximab is classified as a protein-based therapeutic agent, and its administration follows the study protocol. The maximum treatment period for Infliximab is 39 months, with adherence monitoring in place.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression Free Survival (PFS)**, as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and assessed by a Blinded Independent Central Review (BICR). This primary endpoint will measure the time from randomization until the first documented progression of disease or death from any cause, whichever occurs first. Additionally, a secondary endpoint of **Overall Survival (OS)** will be evaluated, which measures the time from randomization until death from any cause.

The trial involves a comparison between the combination of durvalumab, tremelimumab, lenvatinib, and Transarterial Chemoembolization (TACE) versus TACE alone in patients with locoregional hepatocellular carcinoma. The efficacy parameters will be collected and analyzed at specified intervals throughout the study duration, with the estimated end date being February 26, 2027. The trial is designed to demonstrate the superiority of the combination therapy over TACE alone in terms of PFS in participants with locoregional hepatocellular carcinoma.