A Phase 2, Randomized Study to Evaluate the Optimized Dose, Safety, and Efficacy of Livmoniplimab in Combination with Budigalimab for locally advanced or Metastatic Hepatocellular Carcinoma patients who have progressed after an approved immune checkpoint inhibitor containing regimen in First-Line HCC

The primary objective of this Phase 2, randomized study is to optimize the **livmoniplimab** dose in combination with **budigalimab** and identify the recommended phase 3 dose for patients with locally advanced or metastatic **Hepatocellular Carcinoma** (HCC) who have progressed after an immune checkpoint inhibitor-containing regimen in first-line HCC. Additionally, the study aims to evaluate the efficacy of this combination therapy as measured by the rate of best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as determined by investigators. This is clinically relevant as it seeks to improve treatment outcomes for HCC patients who have limited options after first-line therapy failure.

Secondary objectives include:

• Evaluating the efficacy of livmoniplimab in combination with budigalimab as measured by the duration of response (DoR), progression-free survival (PFS), and overall survival (OS) as determined by investigators.
• Assessing the safety, tolerability, immunogenicity, and pharmacokinetics (PK) of the combination therapy.

The clinical trial involves a total of **57 participants** diagnosed with **Hepatocellular Carcinoma** (HCC). The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having a Child-Pugh A classification and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. All participants have previously received an immune checkpoint inhibitor as part of their first-line HCC treatment regimen. The trial excludes individuals with symptomatic, untreated, or actively progressing central nervous system metastases. Participants are required to have adequate hematologic and end-organ function and must undergo a tissue biopsy at screening. The study does not include vulnerable populations, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is a **Phase 2**, randomized, double-blind, controlled study designed to evaluate the optimized dose, safety, and efficacy of **livmoniplimab** in combination with **budigalimab** for patients with locally advanced or metastatic **hepatocellular carcinoma** (HCC) who have progressed after an approved immune checkpoint inhibitor regimen in first-line HCC treatment. The trial aims to identify the recommended phase 3 dose and assess the efficacy of the combination therapy, as measured by the best overall response (BOR) of confirmed complete response (CR) or partial response (PR) determined by investigators. The trial is expected to run from November 15, 2023, to December 23, 2026, with a maximum treatment period of 104 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as Child-Pugh A status, ECOG performance status of 0-1, prior receipt of an immune checkpoint inhibitor, and adequate hematologic and end-organ function. Following randomization, participants will attend regular follow-up visits to monitor safety, efficacy, and any adverse events. The primary endpoint is the BOR of confirmed CR or PR per RECIST 1.1, while secondary endpoints include duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 104 weeks, with conditions for early termination including disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on the participant's best interest. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable insights into the treatment of advanced HCC.

The clinical trial involves the administration of **Kisplyx** 4 mg hard capsules, which contain the active substance **lenvatinib**. This medication is provided in the form of hard capsules and is administered orally. The maximum daily dose is 12 mg, with a total maximum dose of 8.75 grams over the treatment period. The treatment duration is set for a maximum of 104 weeks. **Lenvatinib** is a chemical substance and is not formulated for pediatric use. The product is authorized in the EU and is manufactured by EISAI GMBH.

Another treatment used in the trial is **Sorafenib STADA** 200 mg film-coated tablets, containing the active substance **sorafenib**. This medication is also administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 584 grams over the treatment period. The treatment duration is similarly set for a maximum of 104 weeks. **Sorafenib** is a chemical substance, not formulated for pediatric use, and is authorized in Germany. The manufacturer is STADAPHARM GMBH.

The experimental medication **Budigalimab** is provided as a solution for injection or infusion. The active substance is **budigalimab**, a protein-based compound. The administration route is oral, although typically solutions for injection/infusion are administered intravenously. The treatment period is set for a maximum of 104 weeks. This product is not formulated for pediatric use and is manufactured by ABBVIE DEUTSCHLAND GMBH & CO. KG.

**Livmoniplimab** is another experimental medication used in the trial, provided as a solution for infusion. The active substance is **livmoniplimab**, also a protein-based compound. This medication is administered intravenously, with a treatment period set for a maximum of 104 weeks. Like the other treatments, it is not formulated for pediatric use and is manufactured by ABBVIE DEUTSCHLAND GMBH & CO. KG.

In this clinical trial, the primary objective is to optimize the dose of **livmoniplimab** in combination with **budigalimab** and to identify the recommended phase 3 dose for patients with locally advanced or metastatic hepatocellular carcinoma who have progressed after an immune checkpoint inhibitor-containing regimen. The efficacy of the combination is evaluated by the rate of best overall response of confirmed complete response or partial response as determined by investigators.

The efficacy of the investigational combination of **livmoniplimab** and **budigalimab** in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) will be assessed through several endpoints. The primary endpoint is the Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) as determined by investigators using RECIST 1.1 criteria at any time before the initiation of subsequent anticancer therapy. Secondary endpoints include Duration of Response (DoR), Progression-Free Survival (PFS), and Overall Survival (OS). PFS is defined as the time from randomization to the first documentation of disease progression according to RECIST 1.1 or death from any cause, whichever occurs first. OS is defined as the time from randomization until death from any cause.