Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Pembrolizumab

Chlorotrianisene

Liver Extracts

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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

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.

Regorafenib in combination with pembrolizumab

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

Loco-regional therapy

Project Management

Peter R Galle, MD

Richard S Finn, MD

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.

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.

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

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

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.

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.

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.

OS, defined as the time (in months) from the date of randomization until the date of death due to any cause.

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.

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)

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.

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.

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.

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.

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).

Spots Global Cancer Trial Database for regorafenib in combination with pembrolizumab