Regorafenib-pembrolizumab vs. TACE/TARE in Intermediate Stage HCC Beyond Up-to-7

NCT ID: NCT04777851

Last Updated: 2025-05-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 496 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-11
• Study Completion Date: 2026-02-28

Brief Summary

REPLACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of regorafenib and pembrolizumab (Rego-Pembro) versus transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) for the first-line treatment of hepatocellular carcinoma (HCC or liver cancer). Approximately 496 patients in around 80 clinical sites worldwide will be randomized to receive either:

• Investigational arm: Regorafenib in combination with pembrolizumab
• Control arm: Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE)

In both arms, patients will receive trial treatment until progressive disease, unacceptable toxicity, deterioration of patient's condition that warrants permanent trial treatment discontinuation or other treatment discontinuation criteria is met. After trial treatment discontinuation, subsequent treatment will be administered according to the Investigator's clinical judgment.

Detailed Description

REPLACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of systemic therapy with Rego-Pembro versus loco-regional therapy with TACE or TARE, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Approximately 496 patients (~248 in each arm) from approximately 80 sites will be randomized in order to power the trial efficiently to measure a clinically meaningful improvement for the primary endpoint, PFS according to mRECIST based on the Investigator´s assessment.

The trial will include patients who have been diagnosed with intermediate-stage HCC by biopsy, cytology or diagnostic imaging, such as dynamic computed tomography (CT) or magnetic resonance imaging (MRI), according to the criteria of the American Association for the Study of Liver Diseases (AASLD). Patients should have at least one measurable lesion per RECIST 1.1, disease not amenable to curative treatment but amenable to loco-regional therapy with TACE (cTACE or DEB-TACE) or TARE, ECOG PS 0-1, Child-Pugh class A, and beyond up-to-7 criteria.

The trial will include the following phases:

• Screening
• Treatment
• Follow-up

Randomized patients will receive either:

Investigational arm (Arm A):

-Regorafenib at a dose of 90 mg orally q.d. on days 1 to 21 of a 4-week cycle.

In combination with:

-Pembrolizumab 400 mg using a 30-minutes i.v. infusion, on day 1 (D1) of a 6-week cycle.

Control arm (Arm B):

-Patients will be treated with TACE or TARE "on-demand" according to site's standard, with the goal of controlling all known liver lesions.

In both arms, patients will receive trial treatment (Rego-Pembro or TACE/TARE) until PD per mRECIST, unacceptable toxicity, deterioration of patient's condition that warrants permanent trial treatment discontinuation or other treatment discontinuation criteria are met.

Conditions

Carcinoma, Hepatocellular

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Regorafenib + Pembrolizumab

Investigational arm: regorafenib at a dose of 90 mg orally once per day (on days 1 to 21 of a 28-day cycle), in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 of a 6-week cycle.

Group Type: EXPERIMENTAL

Regorafenib in combination with pembrolizumab

Intervention Type: DRUG

Randomized patients will receive regorafenib at a dose of 90 mg per day by mouth on days 1 to 21 of a 28-day cycle, in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 (D1) of a 6-week cycle.

Loco-regional therapy

Control arm: Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.

Group Type: ACTIVE_COMPARATOR

Loco-regional therapy

Intervention Type: PROCEDURE

Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.

Interventions

Regorafenib in combination with pembrolizumab

Randomized patients will receive regorafenib at a dose of 90 mg per day by mouth on days 1 to 21 of a 28-day cycle, in combination with pembrolizumab 400 mg using a 30-minute intravenous infusion, on day 1 (D1) of a 6-week cycle.

Intervention Type: DRUG

Loco-regional therapy

Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.

Intervention Type: PROCEDURE

Other Intervention Names

Stivarga® (regorafenib); Keytruda® (pembrolizumab); Convention transarterial chemoembolization (cTACE); Drug-eluting bead transarterial chemoembolization (DEB-TACE); Transarterial Chemoembolization (TACE); Transarterial radioembolization (TARE)

Eligibility Criteria

Inclusion Criteria

• Signed and dated Patient Informed Consent Form (PICF)
• ≥ 18 years-old at the time of PICF signature
• Confirmed diagnosis of HCC
• Intermediate-stage HCC, defined as follows:

• Multinodular HCC localized to the liver
• No evidence of MVI or EHS
• Not amenable to curative treatment
• Child-Pugh Class A
• ECOG PS 0 or 1
• ALBI grade 1 or 2
• Beyond up-to-seven criteria
• Disease amenable to TACE or TARE and no contradiction to intra-arterial treatment
• Measurable disease by CT or MRI as per RECIST 1.1
• No prior systemic therapy or loco-regional therapy for HCC
• Adequate hematologic and organ function
• Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures
• Women of childbearing potential (CBP) must have confirmed negative serum pregnancy test
• Use of highly-effective contraceptive methods in women of CBP and men
• Patients with hepatitis C virus (HCV) or hepatitis B virus (HBV) infection are eligible if they meet criteria as defined within the protocol

Exclusion Criteria

• No measurable tumor of a diffuse infiltrative HCC type.
• Fibrolamellar HCC, sarcomatoid HCC or mixed hepatocellular/ cholangiocarcinoma subtypes.
• Clinically meaningful ascites.
• Prior treatment with regorafenib, a PD-1, PD-L1/PD-L2, or cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to randomization.
• Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids.
• Requirement of systemic treatment with either corticosteroids or other immunosuppressive medications ≤ 14 days prior to randomization.
• Interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, or clinically significant acute lung diseases.
• Cardiovascular conditions as defined within the protocol.
• Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed ≤ 2 years before randomization.
• Persistent proteinuria of NCI-CTCAE v5.0 Grade 3.
• Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

Translational Research in Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter R Galle, MD

Role: STUDY_CHAIR

University Medical Center, Mainz, Germany

Richard S Finn, MD

Role: STUDY_CHAIR

UCLA Department of Medicine, Division of Hematology-Oncology

Locations

UCLA Santa Monica Hematology Oncology

Santa Monica, California, United States

UCL SAINT LUC - UC Louvain

Brussels, , Belgium

Antwerp University Hospital

Edegem, , Belgium

CHU Amiens-Picardie

Amiens, , France

Hôpital Beaujon - APHP

Clichy, , France

Hôpital Henri Mondor

Créteil, , France

JSC VIANI Batumi Referral Hospital

Batumi, , Georgia

Israel-Georgian Medical Research Clinic Healthycore

Tbilisi, , Georgia

Universitätsmedizin: Medizinische Klinik und Poliklinik I

Mainz, , Germany

Humanity and Health Clinical Trial Center

Hong Kong, , Hong Kong

Ospedale Garibaldi Nesima

Catania, , Italy

Institutul Clinic Fundeni

Bucharest, , Romania

Regional Institute of Gastroenterology and Hepatology "Dr Octavian Fodor"

Cluj-Napoca, , Romania

Center of Oncology Euroclinic Victoria Hospital

Iași, , Romania

Clinic for Digestive Surgery, University Clinical Center of Serbia

Belgrade, , Serbia

Institue of Oncology Vojvodine Sremska Kamenica (Oncology Institute of Volvodina)

Kamenitz, , Serbia

Inje University Haeundae Paik Hospital

Busan, , South Korea

Cha Bundang Medical Center

Seongnam-si, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Hospital Universitario La Paz

Madrid, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

National Taiwan University Hospital

Taipei, , Taiwan

Chang Gung Memorial Hospital - Linkou

Taoyuan District, , Taiwan

Gülhane Eğitim ve Araştırma Hastanesi

Ankara, , Turkey (Türkiye)

Gazi University MF

Ankara, , Turkey (Türkiye)

Koc University Hospital

Istanbul, , Turkey (Türkiye)

Countries

United States; Belgium; France; Georgia; Germany; Hong Kong; Italy; Romania; Serbia; South Korea; Spain; Taiwan; Turkey (Türkiye)

Other Identifiers

EU CT # 2022-501969-42-00

Identifier Type: OTHER

Identifier Source: secondary_id

TRIO041

Identifier Type: -

Identifier Source: org_study_id