What is the mechanism of action of this treatment?

The most common treatments for Hepatocellular Carcinoma (HCC) include multi-kinase inhibitors like regorafenib and immune checkpoint inhibitors like pembrolizumab. Regorafenib works by inhibiting multiple protein kinases involved in tumor angiogenesis, oncogenesis, and the tumor microenvironment, thereby slowing tumor growth and spread. Pembrolizumab, an immune checkpoint inhibitor, blocks the PD-1 pathway, enhancing the immune system's ability to detect and destroy cancer cells. These mechanisms are crucial for HCC patients as they target the cancer's ability to grow and evade the immune system, offering potential for improved outcomes and survival.

What side effects are associated with this type of intervention?

The most common treatments for Hepatocellular Carcinoma (HCC) include multi-kinase inhibitors like regorafenib, sorafenib, and lenvatinib, which often cause side effects such as hypertension, hand-foot skin reactions, diarrhea, fatigue, and liver dysfunction. Immune checkpoint inhibitors like pembrolizumab and nivolumab can lead to immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and skin reactions. Both treatment types require careful monitoring due to their significant toxicities.

What prior FDA approvals exist?

The FDA has approved several treatments for hepatocellular carcinoma (HCC) that involve multi-kinase inhibition and immune checkpoint inhibition. Sorafenib (Nexavar) was the first multi-kinase inhibitor approved for advanced HCC, targeting RAF kinase and VEGFR. Lenvatinib (Lenvima) is another multi-kinase inhibitor approved for first-line treatment of unresectable HCC. For immune checkpoint inhibition, pembrolizumab (Keytruda) and nivolumab (Opdivo) have been approved for HCC patients who have been previously treated with sorafenib. These treatments are similar to the investigational combination of regorafenib and pembrolizumab, which combines multi-kinase inhibition with immune checkpoint blockade.

What other types of research exist?

Promising novel alternatives to Regorafenib and Pembrolizumab for Hepatocellular Carcinoma patients include Atezolizumab combined with Bevacizumab, which has shown significant efficacy in clinical trials. Additionally, Lenvatinib combined with Pembrolizumab is another promising option, demonstrating improved outcomes in advanced HCC. These combinations leverage both anti-angiogenic and immune checkpoint inhibition mechanisms, offering a comprehensive approach to treatment.

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Checkpoint Inhibitor

Regorafenib + Pembrolizumab vs. Loco-Regional Therapy for Liver Cancer (REPLACE Trial)

Phase 3

Recruiting

Research Sponsored by Translational Research in Oncology

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Not amenable to curative treatment

Disease amenable to TACE or TARE and no contradiction to intra-arterial treatment

Must not have

No measurable tumor of a diffuse infiltrative HCC type

Cardiovascular conditions as defined within the protocol

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3.5 years

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial compares a drug combination (Regorafenib and Pembrolizumab) with localized treatments for liver cancer. It targets patients with intermediate-stage liver cancer that can't be cured with surgery. The drug combination works by stopping cancer growth and boosting the immune system, while the localized treatments directly target the liver cancer.

Who is the study for?

This trial is for adults with confirmed intermediate-stage hepatocellular carcinoma (HCC) who haven't had prior systemic or loco-regional therapy. They should be in good physical condition, have liver cancer that's not curable by surgery, and can't have certain autoimmune diseases or recent major surgeries. Women must not be pregnant and participants must agree to use effective contraception.

What is being tested?

The REPLACE trial compares Regorafenib with pembrolizumab (Rego-Pembro) against transarterial chemoembolization (TACE) or radioembolization (TARE). It aims to find out which treatment is better as a first-line option for liver cancer. Patients will continue treatments until disease progression or unacceptable side effects occur.

What are the potential side effects?

Possible side effects include fatigue, diarrhea, high blood pressure from Regorafenib; immune-related reactions like skin issues, thyroid changes from pembrolizumab; and abdominal pain or fever post TACE/TARE procedures. Side effects vary based on the individual's reaction to the treatment.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My condition cannot be cured with treatment.

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My condition can be treated with TACE or TARE and I have no issues with treatments given through arteries.

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My liver cancer is confined to the liver and has multiple nodules.

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My liver functions well despite my illness.

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I am 18 years old or older.

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I am fully active or restricted in physically strenuous activity but can do light work.

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I have not had any treatment for liver cancer before.

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I have been diagnosed with liver cancer.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My liver cancer is not the widespread type that can be measured.

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My heart condition fits the study's specific requirements.

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I do not have serious lung conditions like fibrosis or uncontrolled lung disease.

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My liver cancer is of a specific rare type.

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I have previously been treated with specific immune system targeting drugs.

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I have significant fluid buildup in my abdomen.

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I have severe protein in my urine.

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I have an autoimmune disease that could come back or affects my organs.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 3.5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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

Secondary study objectives

Change from Baseline in Health-Related Quality of Life as Assessed by the EuroQol's 5-level EQ-5D Health Questionnaire (EQ-5D-5L)

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)

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)

+7 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Regorafenib + PembrolizumabExperimental Treatment1 Intervention

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 II: Loco-regional therapyActive Control1 Intervention

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

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Hepatocellular Carcinoma (HCC) include multi-kinase inhibitors like regorafenib and immune checkpoint inhibitors like pembrolizumab. Regorafenib works by inhibiting multiple protein kinases involved in tumor angiogenesis, oncogenesis, and the tumor microenvironment, thereby slowing tumor growth and spread. Pembrolizumab, an immune checkpoint inhibitor, blocks the PD-1 pathway, enhancing the immune system's ability to detect and destroy cancer cells. These mechanisms are crucial for HCC patients as they target the cancer's ability to grow and evade the immune system, offering potential for improved outcomes and survival.

Role of cellular, molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era.