A phase III, multicenter, randomized, open-label trial to evaluate the safety and efficacy of systemic therapy with regorafenib and pembrolizumab, versus locoregional therapy with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), for the first-line treatment of intermediate-stage hepatocellular carcinoma with beyond up-to-7 criteria (REPLACE).

The primary objective of this study is to compare **progression-free survival** (PFS) for the combination of regorafenib and pembrolizumab (Rego-Pembro) versus transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) in patients with intermediate-stage **hepatocellular carcinoma** (HCC), based on the investigator's assessment using modified RECIST (mRECIST) criteria for HCC. This comparison is clinically relevant as it aims to determine the efficacy of systemic therapy with Rego-Pembro compared to locoregional therapies, potentially influencing first-line treatment strategies for this patient population.

Secondary objectives include:

• Comparing PFS for Rego-Pembro versus TACE/TARE based on independent central review (BICR) assessment.
• Comparing overall survival (OS) for Rego-Pembro versus TACE/TARE.
• Evaluating the two treatment arms with respect to objective response rate (ORR).
• Evaluating the two treatment arms with respect to time to unTACEable progression (TTUP).
• Evaluating the two treatment arms with respect to duration of response (DOR).
• Evaluating safety and tolerability of the trial treatments.

The clinical trial involves a total of **338 participants** diagnosed with **intermediate-stage hepatocellular carcinoma** that exceeds the up-to-seven criteria. The study population includes both male and female subjects, aged 18 years and older, who are in generally good health as indicated by a Child-Pugh Class A status and an ECOG performance status of 0 or 1. Participants were selected based on their confirmed diagnosis of hepatocellular carcinoma, with disease localized to the liver and no evidence of macrovascular invasion or extrahepatic spread. The trial includes individuals with hepatitis C or B virus infections, provided they meet specific protocol criteria. Participants must have measurable disease by CT or MRI and have not received prior systemic or loco-regional therapy for hepatocellular carcinoma. The trial population is characterized by adequate hematologic and organ function, and the ability to comply with trial procedures. Both genders are included, with women of childbearing potential required to use highly effective contraceptive methods and have a confirmed negative serum pregnancy test. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups.

The clinical trial is a **randomized**, open-label, phase III study designed to evaluate the safety and efficacy of systemic therapy with **regorafenib** and **pembrolizumab** compared to locoregional therapy with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) for the first-line treatment of intermediate-stage **hepatocellular carcinoma** with beyond up-to-7 criteria. The trial aims to compare progression-free survival (PFS) between the two treatment arms, assessed by the investigator using modified RECIST (mRECIST) criteria for hepatocellular carcinoma. The trial is expected to commence recruitment in March 2024 and conclude by April 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and disease stage. The inclusion criteria require participants to have a confirmed diagnosis of intermediate-stage hepatocellular carcinoma, be at least 18 years old, and have adequate hematologic and organ function, among other conditions. Women of childbearing potential must have a negative serum pregnancy test and use highly effective contraceptive methods. The trial excludes individuals with prior systemic or locoregional therapy for hepatocellular carcinoma.

Following the screening visit, eligible participants will be randomized to receive either the systemic therapy or locoregional therapy. The trial will include regular follow-up visits to monitor treatment response, safety, and any adverse events. These visits will involve clinical assessments, laboratory tests, and imaging studies to evaluate disease progression. The primary endpoint is PFS, defined as the time from randomization to progressive disease or death from any cause. Secondary endpoints include overall survival (OS), objective response rate (ORR), time to untreatable progression (TTUP), duration of response (DOR), and safety assessments.

The expected duration of participant involvement in the trial is up to 108 weeks for those receiving systemic therapy and up to 36 weeks for those receiving locoregional therapy. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **pembrolizumab**, marketed under the name Keytruda, which is a **monoclonal antibody**. Keytruda is provided as a 25 mg/mL concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 400 mg, with a total maximum dose of 7200 mg over a treatment period of up to 108 weeks. The product is manufactured by Merck Sharp & Dohme BV and is authorized for use in the European Union under the marketing authorization number EU/1/15/1024/002. The administration of Keytruda requires careful monitoring to ensure compliance with the dosing schedule and to manage any potential adverse effects.

Additionally, the trial includes the use of **regorafenib**, identified by the sponsor product code BAY 734506. Regorafenib is a **chemical entity** and functions as a multikinase inhibitor. It is provided in the form of film-coated tablets for oral administration. The maximum daily dose is 90 mg, with a total maximum dose of 68040 mg over a treatment period of up to 36 weeks. The product is manufactured by Bayer AG. As with pembrolizumab, participant compliance with the dosing schedule is crucial, and monitoring is necessary to manage any side effects and ensure the efficacy of the treatment.

The trial also includes a comparator treatment involving locoregional therapies such as transarterial chemoembolization (TACE) or transarterial radioembolization (TARE). These non-experimental treatments are standard-of-care therapies for intermediate-stage hepatocellular carcinoma and serve as a benchmark to evaluate the efficacy and safety of the experimental systemic therapy with regorafenib and pembrolizumab.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization until the date of progressive disease or death from any cause, whichever occurs first. This will be assessed locally by the Investigator using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for hepatocellular carcinoma (HCC).

Secondary endpoints include PFS assessed by both the Investigator and Blinded Independent Central Review (BICR) per RECIST 1.1 and mRECIST, Overall Survival (OS) from randomization until the date of death, and Objective Response Rate (ORR) per RECIST v.1.1 and mRECIST as assessed by the Investigator and BICR. Time to Unacceptable Progression (TTUP) will be measured from randomization until any protocol criteria related to liver function or HCC are met. Duration of Response (DOR) will be evaluated per Investigator assessment or death in patients who achieved a best overall response of Complete Response (CR) or Partial Response (PR). Safety will be monitored by assessing the frequency and severity of adverse events and laboratory abnormalities.