A PHASE IB/II, OPEN-LABEL, MULTICENTER, RANDOMIZED PLATFORM STUDY EVALUATING THE EFFICACY AND SAFETY OF NEOADJUVANT IMMUNOTHERAPY COMBINATIONS IN PATIENTS WITH SURGICALLY RESECTABLE HEPATOCEULLULAR CARCINOMA (MORPHEUS-NEO HCC)

The primary objective of this study is to evaluate the **efficacy** of neoadjuvant immunotherapy-based treatment combinations in patients with surgically resectable hepatocellular carcinoma, specifically by assessing the major pathologic response (MPR) rate. This is clinically relevant as achieving a higher MPR rate may correlate with improved surgical outcomes and long-term survival in patients undergoing resection for hepatocellular carcinoma.

Secondary objectives include:

• Evaluating the efficacy of these treatment combinations based on the pathologic complete response (pCR) rate, relapse-free survival (RFS), event-free survival (EFS), overall survival (OS), objective response rate (ORR), the proportion of participants downstaged to within Milan criteria, and R0 resection rate.
• Assessing the safety and tolerability of the treatment combinations by examining the incidence, nature, and severity of adverse events, serious adverse events, and immune-related adverse events.
• Evaluating surgical feasibility, outcomes, morbidity, and mortality, focusing on the proportion of participants with delayed or canceled surgery due to treatment-related adverse events, length of surgical delay, duration of surgery, length of hospital stay, surgical approach, extent of surgery, intraoperative blood loss, need for intraoperative blood transfusion, post-operative surgical complication rates according to Clavien-Dindo surgical classification, and post-operative mortality.

The clinical trial involves a total of **88 participants** diagnosed with **Hepatocellular Carcinoma**. 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 a confirmed diagnosis of Hepatocellular Carcinoma, the potential for surgical resection with curative intent, and measurable disease according to RECIST v1.1. The trial includes individuals with an Eastern Cooperative Oncology Group Performance Status of 0 or 1 and Child-Pugh Class A, ensuring a relatively stable health status. Participants have not received prior locoregional or systemic treatment for Hepatocellular Carcinoma. The trial also considers vulnerable populations, although specific lifestyle factors such as diet or physical activity are not detailed in the available data.

The clinical trial is designed as a **randomized**, open-label, multicenter platform study to evaluate the efficacy and safety of neoadjuvant immunotherapy combinations in patients with surgically resectable **hepatocellular carcinoma**. The trial aims to assess the major pathologic response (MPR) rate as the primary endpoint, with secondary endpoints including pathologic complete response (pCR) rate, recurrence-free survival (RFS), event-free survival (EFS), overall survival (OS), and overall response rate (ORR). The study will also evaluate the proportion of participants downstaged to within Milan criteria, R0 resection rate, and the incidence and severity of adverse events.

The trial is expected to commence recruitment on December 31, 2023, and is estimated to conclude by November 30, 2027. Participants will be involved in the study from the initial screening visit through to the end-of-study visit, with the duration of individual participation dependent on the treatment regimen and follow-up schedule. The inclusion visit will involve screening for eligibility based on criteria such as a confirmed diagnosis of hepatocellular carcinoma, measurable disease according to RECIST v1.1, and an ECOG Performance Status of 0 or 1. Follow-up visits will be scheduled to monitor treatment response and adverse events, with the end-of-study visit marking the completion of the participant's involvement.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will utilize intravenous infusion as the route of administration for the investigational products, which include **bevacizumab**, **tiragolumab**, **atezolizumab**, and RO7247669. The study is not classified as low intervention and is part of a confirmatory/registrational trial with ongoing development for the investigational molecules. The trial is conducted under the sponsorship of Roche Registration GmbH and F. Hoffmann-La Roche Ltd, with the investigational products being tested for their potential to improve surgical outcomes and overall survival in patients with hepatocellular carcinoma.

The clinical trial involves the administration of several experimental medications, each delivered as a **solution for infusion**. **Avastin**, with the active substance **bevacizumab**, is provided as a 25 mg/ml concentrate for solution for infusion. It is administered via **IV infusion**. The pharmaceutical form is a concentrate for solution for infusion, and it is not a pediatric formulation. The product is authorized under the marketing authorization number EU/1/04/300/002 and is manufactured by Roche Registration GmbH.

**Tiragolumab** is another investigational product in this study, presented as a concentrate for solution for infusion. The active substance is **tiragolumab**, and it is administered through **IV infusion**. The product is identified by the sponsor product code RO 709-2284/F03-01 and is produced by F. Hoffmann-La Roche Ltd. This product is not a pediatric formulation and is currently in the authorization process.

**Tecentriq**, containing the active substance **atezolizumab**, is provided as a 1,200 mg concentrate for solution for infusion. It is administered via **IV infusion**. The pharmaceutical form is a solution for infusion, and it is not a pediatric formulation. The product is authorized under the marketing authorization number EU/1/17/1220/001 and is manufactured by Roche Registration GmbH.

**RO7247669**, also known as **TOBEMSTOMIG**, is included in the trial as a solution for infusion. The active substance is **RO7247669**, and it is administered through **IV infusion**. The product is identified by the sponsor product code RO 724-7669/F01-01 and is produced by F. Hoffmann-La Roche Ltd. This product is not a pediatric formulation and is currently in the authorization process.

All investigational products are administered via the intravenous route, ensuring consistent delivery of the active substances. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the neoadjuvant immunotherapy-based treatment combinations in patients with surgically resectable **hepatocellular carcinoma** will be assessed primarily through the major pathologic response (MPR) rate. This primary endpoint will provide a direct measure of the treatment's impact on tumor pathology. Secondary endpoints include the pathologic complete response (pCR) rate, recurrence-free survival (RFS), event-free survival (EFS), overall survival (OS), and objective response rate (ORR). Additionally, the study will evaluate the proportion of participants downstaged to within Milan criteria, the R0 resection rate, and various surgical and post-operative outcomes.

The incidence, nature, and severity of adverse events, including serious and immune-related adverse events, will be monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). The severity of cytokine release syndrome (CRS) will be assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading Scale. The study will also track the proportion of participants with delayed or canceled surgery due to treatment-related adverse events, as well as surgical metrics such as the length of surgical delay, duration of surgery, length of hospital stay, surgical approach, extent of surgery, intraoperative blood loss, and the need for intraoperative blood transfusion. Post-operative surgical complication rates will be classified according to the Clavien-Dindo surgical classification, and post-operative mortality will be recorded.