Phase III Randomized Study of Durvalumab and Tremelimumab Versus Sorafenib in First-Line Treatment of Unresectable Advanced Hepatocellular Carcinoma

The primary objective of this study is to assess the **efficacy** of durvalumab plus tremelimumab combination therapy compared with sorafenib in patients with advanced hepatocellular carcinoma (HCC). This is clinically relevant as it aims to determine if the combination therapy can provide a more effective first-line treatment option for patients with unresectable liver cancer, potentially improving survival outcomes and quality of life.

Secondary objectives include:

• Assessing the efficacy of durvalumab monotherapy compared with sorafenib.
• Evaluating the safety and tolerability profile across all treatment arms.
• Assessing the efficacy of durvalumab monotherapy and durvalumab plus tremelimumab combination therapy compared with sorafenib by PD-L1 expression.
• Evaluating disease-related symptoms, impacts, and health-related quality of life (HRQoL) in durvalumab monotherapy and durvalumab plus tremelimumab combination therapy compared with sorafenib.
• Evaluating the population pharmacokinetics (PK) and pharmacodynamics of durvalumab monotherapy and durvalumab plus tremelimumab combination therapy.
• Investigating the immunogenicity of durvalumab monotherapy and durvalumab plus tremelimumab combination therapy.

The clinical trial involves a total of **1302 participants** diagnosed with **advanced hepatocellular carcinoma (HCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a histopathological confirmation of HCC, no prior systemic therapy for HCC, and a classification of Barcelona Clinic Liver Cancer (BCLC) stage B or C. Additionally, participants were required to have a Child-Pugh Score class A and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment. The trial population includes individuals from a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed. The selection process ensures a focus on individuals who meet the outlined health status and disease progression criteria.

The clinical trial is designed as a **randomized**, open-label, multi-center Phase III study to evaluate the efficacy and safety of **durvalumab** and **tremelimumab** as a first-line treatment in patients with advanced **hepatocellular carcinoma** (HCC). The trial aims to compare the combination therapy of durvalumab plus tremelimumab against **sorafenib**, the standard first-line treatment. The primary endpoint is overall survival, defined as the time from randomization until death from any cause. Secondary endpoints include progression-free survival, time to progression, objective response rate, disease control rate, and duration of response. The estimated trial duration extends until December 31, 2024, with recruitment anticipated to start on June 18, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histopathological confirmation of HCC, no prior systemic therapy for HCC, and an ECOG performance status of 0 or 1. Follow-up visits will be scheduled to monitor treatment response and safety, with the end-of-study visit marking the conclusion of participant involvement. The expected length of participant involvement will vary depending on individual response and progression, with the possibility of early termination due to adverse events, withdrawal of consent, or disease progression.

The trial involves the administration of durvalumab and tremelimumab via **intravenous** infusion, while sorafenib is administered orally in the form of film-coated tablets. The study does not include any pediatric formulations, and all products are authorized for use in the trial. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to assess the therapeutic outcomes of the investigational treatments. The trial is not classified as low intervention, reflecting its comprehensive approach to evaluating the potential benefits of the combination therapy in a population with advanced HCC.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Mycophenolate Mofetil** is provided in the form of 500 mg film-coated tablets. This medication is administered orally, with the dosage and frequency determined by the study protocol. The active substance, mycophenolate mofetil, is of chemical origin and is manufactured by Morningside Healthcare Ltd. The maximum treatment period is not specified, allowing for flexibility in dosing schedules as per clinical requirements.

**Tremelimumab** is administered as a 20 mg/mL concentrate for solution for infusion. This protein-based medication is delivered intravenously, with a maximum daily dose of 300 mg. The product is developed by AstraZeneca AB and is used as part of the experimental treatment regimen. The administration schedule is designed to optimize therapeutic outcomes while monitoring participant compliance closely.

**Durvalumab** is provided as a 50 mg/mL concentrate for solution for infusion, also administered intravenously. The maximum daily dose is set at 1500 mg. This protein-based therapeutic is produced by AstraZeneca AB and serves as a key component of the experimental treatment strategy. The dosing schedule is tailored to the study's objectives, ensuring adherence to the protocol.

**Infliximab** is available as a 100 mg powder for concentrate for solution for infusion. This protein-based medication is administered intravenously, with the dosing regimen determined by the study protocol. Manufactured by Pfizer Europe MA EEIG, infliximab is used as an auxiliary treatment in the trial, with compliance monitored throughout the study duration.

**Sorafenib** is administered in the form of 200 mg film-coated tablets. This chemical-based medication is taken orally, with a maximum daily dose of 400 mg. Produced by Bayer AG, sorafenib serves as a comparator treatment in the trial. The dosing schedule is designed to align with the study's objectives, ensuring participant adherence and monitoring.

The efficacy of the combination therapy of **durvalumab** and **tremelimumab** compared to **sorafenib** in patients with advanced hepatocellular carcinoma will be assessed through a series of primary and secondary endpoints. The primary endpoint is overall survival (OS), defined as the time from the date of randomization until death from any cause. Secondary endpoints include progression-free survival (PFS), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and duration of response (DoR).

These efficacy parameters will be measured and collected at specified intervals throughout the trial. The analysis will involve comparing the outcomes between the treatment groups to determine the relative efficacy of the combination therapy. The trial is designed as a randomized, open-label, multi-center Phase III study, ensuring a robust evaluation of the treatment's impact on the specified endpoints.