Phase 1/2 Randomized, Placebo-Controlled Study of Nivolumab, Relatlimab, and Bevacizumab in Treatment-Naive Advanced/Metastatic Hepatocellular Carcinoma

The primary objective of this study is to determine the **RP2D** (recommended Phase 2 dose) of the triplet combination of relatlimab, nivolumab, and bevacizumab in participants with advanced/metastatic **hepatocellular carcinoma** (HCC) who have not received prior systemic therapy. Additionally, the study aims to evaluate the **ORR** (objective response rate) of the triplet combination relative to the doublet combination of nivolumab and bevacizumab in all randomized participants with advanced/metastatic HCC who have not received prior systemic therapy. These objectives are clinically relevant as they aim to establish an effective dosing regimen and assess the therapeutic efficacy of these combinations in a first-line treatment setting for advanced HCC, potentially improving patient outcomes.

Secondary objectives include:

• Estimating key efficacy endpoints of the relatlimab, nivolumab, and bevacizumab triplet combination and the nivolumab and bevacizumab doublet combination in all randomized participants with advanced/metastatic HCC who have not received prior systemic therapy and in those who express **LAG-3** (lymphocyte activation gene-3) (≥ 1%) by immunohistochemistry.
• Determining the safety and tolerability of the relatlimab, nivolumab, and bevacizumab triplet combination in all treated participants with advanced/metastatic HCC who have not received prior systemic therapy.

The clinical trial involves a total of **109 participants** diagnosed with **advanced/metastatic hepatocellular carcinoma (HCC)**. The study population includes both male and female subjects, aged 18 years and older, who have not received prior systemic therapy for their condition. Participants were selected based on specific criteria, including an **ECOG performance status** of 0-1 and a **Child-Pugh score** of A, indicating a relatively preserved liver function. The trial also considers individuals at **Barcelona Clinical Liver Cancer stage B or C**. The selection process ensures a diverse representation of the disease stage and liver function status. Participants' lifestyle factors such as diet and physical activity are not specified, but the inclusion of a vulnerable population is noted. The trial aims to evaluate the efficacy of a triplet combination therapy in this specific patient group.

The clinical trial is designed to evaluate the safety and efficacy of a combination therapy involving **nivolumab**, **relatlimab**, and **bevacizumab** in patients with advanced or metastatic **hepatocellular carcinoma** (HCC) who have not received prior systemic therapy. This is a Phase 1/2, randomized, double-blind, placebo-controlled study. The trial aims to determine the recommended Phase 2 dose (RP2D) and assess the objective response rate (ORR) of the triplet combination compared to a doublet combination of nivolumab and bevacizumab. The study is expected to run from March 18, 2022, to January 18, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous treatment history, and disease stage. The trial will include multiple follow-up visits to monitor safety and efficacy endpoints, including dose-limiting toxicities and progression-free survival. The end-of-study visit will conclude the participant's involvement, assessing long-term safety and treatment outcomes. The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment regimen.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, disease progression, or if they withdraw consent. The primary endpoints will focus on safety and efficacy, while secondary endpoints will include additional efficacy measures and a comprehensive safety evaluation. The trial will ensure rigorous monitoring to maintain the integrity of the data and the safety of the participants throughout the study duration.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Relatlimab** is an experimental medication used in this study. It is provided as a **solution for injection** and is administered via **intravenous use**. The active substance in Relatlimab is a protein of other origin, and it is produced by Bristol-Myers Squibb International Corporation. The sponsor product codes for Relatlimab are BMS-986016 and BMS-986016-01. The frequency and specific dosing schedule for Relatlimab are determined as per the study protocol, with compliance monitored throughout the trial.

Another experimental treatment in the trial is **Nivolumab**, marketed under the name OPDIVO. It is supplied as a **concentrate for solution for infusion** and is also administered intravenously. The active substance, **Nivolumab**, is a protein of other origin, manufactured by Bristol-Myers Squibb Pharma EEIG. The sponsor product code for Nivolumab is BMS-936558. The dosing schedule and administration frequency are outlined in the study protocol, with adherence monitored to ensure participant compliance.

**Bevacizumab**, known commercially as Avastin, is also part of the experimental treatment regimen. It is provided as a **concentrate for solution for infusion** and administered via **intravenous use**. The active substance, **Bevacizumab**, is a protein of other origin, produced by Roche Registration GmbH. The administration and dosing schedule for Bevacizumab are specified in the study protocol, with compliance monitoring in place to ensure adherence to the treatment regimen.

The non-experimental treatment used in this study is a **0.9% Sodium Chloride Injection**, which serves as a placebo. It is administered intravenously, and its pharmaceutical form is not specified. The placebo is used to maintain blinding in the study and to provide a control for evaluating the efficacy and safety of the experimental treatments. The administration schedule for the placebo is aligned with that of the experimental treatments to ensure consistency in the trial design.

Efficacy in this clinical trial will be assessed primarily by evaluating the **objective response rate (ORR)**, which is the proportion of participants who respond to treatment. This assessment will be conducted in participants with advanced/metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy. The trial will compare the ORR of the triplet combination of relatlimab, nivolumab, and bevacizumab against the doublet combination of nivolumab and bevacizumab. The efficacy evaluation will be conducted in two parts: Part 1 will focus on analyzing the rate of dose-limiting toxicities to confirm safety, and Part 2 will proceed with the efficacy assessment once safety is confirmed.

Secondary efficacy endpoints include the evaluation of **progression-free survival (PFS)**, which measures the time from the start of treatment until the worsening of the disease. These endpoints will be assessed in both groups of participants. The trial will also monitor safety by reviewing adverse events, serious adverse events, and immune-mediated adverse events from the first dose to 30 or 135 days after the last dose. The trial is designed to provide comprehensive data on the efficacy and safety of the treatment combinations in the specified patient population.