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

NCT04777851 | Terminated Phase 3 DMC FDA Drug

• 2 other identifiers: TRIO041EU CT # 2022-501969-42-00
• Study Type: interventional
• Target: 45
• Locations: 13 countries
• Sites: 26

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.

Conditions

Carcinoma, Hepatocellular

Keywords

Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult

Outcome Measures

Primary Outcomes (1)

• Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC

  PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using mRECIST.

  up to 3.5 years

Secondary Outcomes (10)

• Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  up to 3.5 years

• Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1

  up to 3.5 years

• Overall Survival (OS) of Intermediate-Stage HCC (Rego-Pembro versus Loco-regional Therapy)

  up to 3.5 years

• Overall Response Rate (ORR) Assessed by Investigator and Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1

  up to 3.5 years

• Time to unTACEable Progression (TTUP)

  up to 3.5 years

Study Arms (2)

Regorafenib + Pembrolizumab

EXPERIMENTAL

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.

Drug: Regorafenib in combination with pembrolizumab

Loco-regional therapy

ACTIVE COMPARATOR

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

Procedure: Loco-regional therapy

Interventions

Loco-regional therapy PROCEDURE

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

Also known as: Convention transarterial chemoembolization (cTACE), Drug-eluting bead transarterial chemoembolization (DEB-TACE), Transarterial Chemoembolization (TACE), Transarterial radioembolization (TARE)

Loco-regional therapy

Regorafenib in combination with pembrolizumab 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.

Also known as: Stivarga® (regorafenib), Keytruda® (pembrolizumab)

Regorafenib + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Translational Research in Oncology: lead
• Bayer: collaborator

Study Sites (26)

UCLA Santa Monica Hematology Oncology

Santa Monica, California, 90404, United States

Location

UCL SAINT LUC - UC Louvain

Brussels, 1200, Belgium

Location

Antwerp University Hospital

Edegem, 2650, Belgium

Location

CHU Amiens-Picardie

Amiens, 80054, France

Location

Hôpital Beaujon - APHP

Clichy, 92110, France

Location

Hôpital Henri Mondor

Créteil, 94010, France

Location

JSC VIANI Batumi Referral Hospital

Batumi, 6010, Georgia

Location

Israel-Georgian Medical Research Clinic Healthycore

Tbilisi, 0112, Georgia

Location

Universitätsmedizin: Medizinische Klinik und Poliklinik I

Mainz, D-55131, Germany

Location

Humanity and Health Clinical Trial Center

Hong Kong, 999077, Hong Kong

Location

Ospedale Garibaldi Nesima

Catania, 95122, Italy

Location

Institutul Clinic Fundeni

Bucharest, 22328, Romania

Location

Regional Institute of Gastroenterology and Hepatology "Dr Octavian Fodor"

Cluj-Napoca, 400394, Romania

Location

Center of Oncology Euroclinic Victoria Hospital

Iași, 700106, Romania

Location

Clinic for Digestive Surgery, University Clinical Center of Serbia

Belgrade, Serbia

Location

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

Kamenitz, 21204, Serbia

Location

Inje University Haeundae Paik Hospital

Busan, South Korea

Location

Cha Bundang Medical Center

Seongnam-si, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, South Korea

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

National Taiwan University Hospital

Taipei, 10041, Taiwan

Location

Chang Gung Memorial Hospital - Linkou

Taoyuan District, 333, Taiwan

Location

Gülhane Eğitim ve Araştırma Hastanesi

Ankara, 6010, Turkey (Türkiye)

Location

Gazi University MF

Ankara, 6560, Turkey (Türkiye)

Location

Koc University Hospital

Istanbul, 34010, Turkey (Türkiye)

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

regorafenib; pembrolizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Peter R Galle, MD

  University Medical Center, Mainz, Germany

  STUDY CHAIR

• Richard S Finn, MD

  UCLA Department of Medicine, Division of Hematology-Oncology

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2021
• First Posted: March 2, 2021
• Study Start: October 11, 2023
• Primary Completion: February 26, 2026
• Study Completion: February 26, 2026
• Last Updated: March 9, 2026

Record last verified: 2026-03

Locations

RO (3); FR (3); HK (1); IT (1); GE (2); SE (2); ES (2); TU (3); US (1); DE (1); KR (3); BE (2); TW (2)