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

Carcinoma, Hepatocellular Clinical Trial

— REPLACE  

Official title:

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 or Transarterial Radioembolization, for the First-line Treatment of Intermediate-stage Hepatocellular Carcinoma With Beyond Up-to-7 Criteria

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04777851
• Other study ID #: TRIO041
• Secondary ID: EU CT # 2022-501
• Status: Recruiting
• Phase: Phase 3
• Start date: October 11, 2023
• Est. completion date: April 2027

Study information

• Verified date: June 2024
• Source: Translational Research in Oncology
• Contact: Project Management
• Phone: +33 1 58 10 08 81
• Email: 041[@]trioncology.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 496
• Est. completion date: April 2027
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Drug:
• 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.

Procedure:
• Loco-regional therapy
Patients will be treated with TACE or TARE "on-demand" according to site's standard of practice.

Locations

Country	Name	City	State
Belgium	Hôpital Erasme	Brussels
Belgium	UCL SAINT LUC - UC Louvain	Brussels
Belgium	Antwerp University Hospital	Edegem
France	CHU Amiens-Picardie	Amiens
France	CHU Jean Minjoz	Besançon
France	Hôpital Avicenne - APHP	Bobigny
France	Hôpital Beaujon - APHP	Clichy
France	Hôpital Henri Mondor	Créteil
France	CHU Grenoble Alpes - Site Nord	La Tronche
France	CHU de Nantes - Hôtel-Dieu	Nantes
Georgia	JSC VIANI Batumi Referral Hospital	Batumi
Georgia	Israel-Georgian Medical Research Clinic Healthycore	Tbilisi
Georgia	New Hospitals	Tbilisi
Germany	University Hospital Bonn	Bonn
Germany	University Hospital Carl Gustav Carus Dresden	Dresden
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	Universitätsklinikum Schleswig-Holstein -Kiel	Kiel
Germany	Universitätsmedizin: Medizinische Klinik und Poliklinik I	Mainz
Hong Kong	Department Of Clinical Oncology, Queen Mary Hospital, University of Hong Kong	Hong Kong
Hong Kong	Humanity and Health Clinical Trial Center	Hong Kong
Hong Kong	Queen Mary Hospital, University of Hong Kong Department of Medicine, Medical Oncology	Hong Kong
Italy	ASST Papa Giovanni XXIII Hospital	Bergamo
Italy	Ospedale Garibaldi Nesima	Catania
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milan
Italy	San Raffaele Hospital	Milan
Italy	Azienda Ospedaliera Universitaria Federico II di Napoli	Napoli
Japan	Chiba University Hospital	Chiba
Japan	Kurume University Hospital	Fukuoka
Japan	Fujita Health University Hospital Department of Gastroenterology and Hepatology	Kutsukake	Toyoake
Japan	Nagoya University Hospital	Nagoya
Japan	Kindai University Hospital	Osaka sayama-shi, Osaka
Japan	Ehime University Hospital	Toon	Ehime
Japan	Toyama University Hospital	Toyama
Japan	Kanagawa Cancer Center	Yokohama
Korea, Republic of	Inje University Haeundae Paik Hospital	Busan
Korea, Republic of	Cha Bundang Medical Center	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Serbia	Clinic for Digestive Surgery, University Clinical Center of Serbia	Belgrade
Serbia	Military Medical Academy	Belgrade
Serbia	Clinical Center Nis	Niš
Serbia	Institue of Oncology Vojvodine Sremska Kamenica (Oncology Institute of Volvodina)	Sremska Kamenica
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Reina Sofía	Córdoba
Spain	Instituto Catalán de Oncología L'Hospitalet	L'Hospitalet De Llobregat
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Puerta de Hierro	Majadahonda
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario Miguel Servet	Zaragoza
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Chi Mei Medical Center-Liuying	Tainan
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital - Linkou	Taoyuan
Taiwan	Taipei Veterans General Hospital	Tapei
Turkey	Ankara City Hospital	Ankara
Turkey	Gazi University MF	Ankara
Turkey	Gülhane Egitim ve Arastirma Hastanesi	Ankara
Turkey	Dicle University MF	Diyarbakir
Turkey	Koc University Hospital	Istanbul
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Miami Cancer Institute	Miami	Florida
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	UCLA Santa Monica Hematology Oncology	Santa Monica	California

Sponsors (2)

Lead Sponsor	Collaborator
Translational Research in Oncology	Bayer

Countries where clinical trial is conducted

United States,  Belgium,  France,  Georgia,  Germany,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Serbia,  Spain,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	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 RECIST 1.1.	up to 3.5 years
Secondary	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	PFS, defined as the time (in months) from the date of randomization until the date of PD or death due to any cause, whichever occurs first. PD will be assessed by BICR using, independently, mRECIST and RECIST 1.1.	up to 3.5 years
Secondary	Overall Survival (OS) of Intermediate-Stage HCC (Rego-Pembro versus Loco-regional Therapy)	OS, defined as the time (in months) from the date of randomization until the date of death due to any cause.	up to 3.5 years
Secondary	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	ORR, defined as the proportion of patients who have a complete response (CR) or partial response (PR) according to RECIST v.1.1 and mRECIST, based on the Investigator's and BICR assessment.	up to 3.5 years
Secondary	Time to unTACEable Progression (TTUP)	To evaluate the two treatment arms (rego-pembro versus loco-regional therapy) with respect to TTUP. TTUP, defined as the time (in months) from the date of randomization until any of the following criteria are met: Factors related to liver function: Decompensated cirrhosis (Child-Pugh class B score > 8), including jaundice, clinical hepatic encephalopathy, and refractory ascites and/or hepatorenal syndrome; Impaired portal-vein blood flow (portal-vein thrombus, hepatofugal blood flow); ECOG PS = 2 Note: transient post-TACE/TARE impairment of liver function of Child-Pugh class B score > 8, that return to pre-TACE/TARE values within 4 weeks of the TACE/TARE session will not qualify as TTUP.; Factors related to HCC: Failure of the treated nodule to achieve Stable Disease (SD), PR or CR by mRECIST; Malignant portal vein thrombosis; Marcovascular invasion (MVI) or Extra-hepatic Spread (EHS)	up to 3.5 years
Secondary	Duration of Response (DOR) of Rego-Pembro Versus Loco-regional Therapy	To evaluate the two treatment arms with respect to DOR. DOR, defined as the time (in months) from first documentation of response (PR or CR) to PD or death, based on Investigator's assessment or death from any cause, in patients who had a best overall response of CR or PR.	up to 3.5 years
Secondary	Number of Patients with Adverse Events as Assessed by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5	The NCI-CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading scale is provided for each AE term with unique clinical descriptions of severity based on this general guideline: Grade 1 (mild) to 5 (death). AEs will be tabulated by treatment arm, system organ class, preferred term, severity, and relationship to treatment.	up to 3.5 years
Secondary	Change from Baseline in the Physical Functioning Sub-scale Score and Global Health Status/Quality of Life Scale Score as assessed by European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)	To evaluate the patient reported outcomes in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by EORTC QLQ C30. EORTC QLQ C30 is a quality-of-life questionnaire to assess patients' physical, psychological and social functions. The questionnaire is composed of functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, and nausea and vomiting), global health status and quality of life scale, also several single-item symptom measures (scaling of items: 1 = Not at all to 4 = Very much; 1 = Very poor to 7 = Excellent). Scores range from 0 to 100, with a high score representing a better health-related quality of life.	up to 3.5 years
Secondary	Change from Baseline in Health-related Quality of Life in Hepatocellular Carcinoma as Assessed by European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire for HCC (EORTC QLQ-HCC18)	To evaluate patient reported outcomes in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by EORTC QLQ-HCC18. EORTC QLQ-HCC18 is an 18-question module specifically to assess symptom burden and impact on health-related quality of life measuring HCC-specific symptoms. The instrument is an 18-item scale, and scores are based on a 4-point Likert scale (with 1 = 'not at all' to 4 = 'very much'); scaled scores range from 0-100 with a higher score indicating worse symptoms.	up to 3.5 years
Secondary	Change from Baseline in Health-Related Quality of Life as Assessed by the EuroQol's 5-level EQ-5D Health Questionnaire (EQ-5D-5L)	To evaluate patient reported outcomes for health-related quality of life in the two treatment arms (rego-pembro versus loco-regional therapy) as assessed by health questionnaire EQ-5D-5L. Each dimension (Mobility, Self-care, Usual activities, Pain & discomfort, Anxiety & depression) in the EQ-5D-5L has five response levels: no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). There are 3,125 possible health states defined by combining one level from each dimension, ranging from 11111 (full health) to 55555 (worst health).	up to 3.5 years