Clinical trial NCT04777851: Regorafenib-pembrolizumab vs. TACE/TARE in Intermediate Stage HCC Beyond Up-to-7
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Carcinoma, Hepatocellular
Keywords: Hepatocellular Carcinoma
Hepatoma
Liver Cancer, Adult
Liver Cell Carcinoma
Liver Cell Carcinoma, Adult
Lead sponsor: Translational Research in Oncology
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2021-03-02
Enrollment: 496
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC
timeFrame: up to 3.5 years
Secondary outcomes:
measure: Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: up to 3.5 years
measure: 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
timeFrame: up to 3.5 years
measure: Overall Survival (OS) of Intermediate-Stage HCC (Rego-Pembro versus Loco-regional Therapy)
timeFrame: up to 3.5 years
measure: 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
timeFrame: up to 3.5 years
measure: Time to unTACEable Progression (TTUP)
timeFrame: up to 3.5 years
measure: Duration of Response (DOR) of Rego-Pembro Versus Loco-regional Therapy
timeFrame: up to 3.5 years
measure: Number of Patients with Adverse Events as Assessed by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5
timeFrame: up to 3.5 years
measure: 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)
timeFrame: up to 3.5 years
measure: 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)
timeFrame: up to 3.5 years
measure: Change from Baseline in Health-Related Quality of Life as Assessed by the EuroQol's 5-level EQ-5D Health Questionnaire (EQ-5D-5L)
timeFrame: up to 3.5 years
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: UCLA Santa Monica Hematology Oncology
state: California
city: Brussels
country: Belgium
facility: UCL SAINT LUC - UC Louvain
city: Edegem
country: Belgium
facility: Antwerp University Hospital
city: Amiens
country: France
facility: CHU Amiens-Picardie
city: Clichy
country: France
facility: Hôpital Beaujon - APHP
city: Créteil
country: France
facility: Hôpital Henri Mondor
city: Batumi
country: Georgia
facility: JSC VIANI Batumi Referral Hospital
city: Tbilisi
country: Georgia
facility: Israel-Georgian Medical Research Clinic Healthycore
city: Mainz
country: Germany
facility: Universitätsmedizin: Medizinische Klinik und Poliklinik I
city: Hong Kong
country: Hong Kong
facility: Humanity and Health Clinical Trial Center
city: Catania
country: Italy
facility: Ospedale Garibaldi Nesima
city: Busan
country: Korea, Republic of
facility: Inje University Haeundae Paik Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Cha Bundang Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
city: Cluj-Napoca
country: Romania
facility: Regional Institute of Gastroenterology and Hepatology "Dr Octavian Fodor"
city: Iaşi
country: Romania
facility: Center of Oncology Euroclinic Victoria Hospital
city: Belgrade
country: Serbia
facility: Clinic for Digestive Surgery, University Clinical Center of Serbia
city: Sremska Kamenica
country: Serbia
facility: Institue of Oncology Vojvodine Sremska Kamenica (Oncology Institute of Volvodina)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou
city: Ankara
country: Turkey
facility: Gülhane Eğitim ve Araştırma Hastanesi
city: Ankara
country: Turkey
facility: Gazi University MF
city: Istanbul
country: Turkey
facility: Koc University Hospital
Study officials:
affiliation: University Medical Center, Mainz, Germany
name: Peter R Galle, MD
role: STUDY_CHAIR
affiliation: UCLA Department of Medicine, Division of Hematology-Oncology
name: Richard S Finn, MD
role: STUDY_CHAIR
References: