Regorafenib + Pembrolizumab vs. Loco-Regional Therapy for Liver Cancer

(REPLACE Trial)

Not currently recruiting at 85 trial locations

Overseen By Project Management

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Translational Research in Oncology

Must not be taking: Corticosteroids, Immunosuppressants, others

Disqualifiers: Autoimmune disease, Invasive malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: up to 3.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatment options for liver cancer. One group will receive regorafenib (a cancer-fighting drug) combined with pembrolizumab (an immune therapy), while the other group will undergo loco-regional therapy, which targets the cancer directly within the liver. The trial aims to determine which treatment is more effective and safer for patients with liver cancer that cannot be treated with surgery. Individuals diagnosed with liver cancer that has not spread outside the liver and have not yet received systemic treatment might be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients access to potentially effective treatments.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic corticosteroids or other immunosuppressive medications within 14 days before randomization. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot be on systemic corticosteroids or other immunosuppressive medications within 14 days before starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using regorafenib and pembrolizumab together is generally safe for people with advanced liver cancer. One study found that the side effects of this combination can be managed. Another study demonstrated that regorafenib, whether used alone or with other treatments, is effective and safe for long-term use in treating advanced cancers.

Patients in previous studies experienced some side effects, but these were usually manageable. This suggests that most people can handle the treatment well, although individual experiences may differ. Discuss any concerns with a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Regorafenib and Pembrolizumab for liver cancer because they offer a fresh approach compared to traditional treatments like surgery, ablation, or chemoembolization. Regorafenib works by inhibiting multiple kinases, which can help slow tumor growth, while Pembrolizumab is an immune checkpoint inhibitor that helps the body's immune system attack cancer cells more effectively. This combination has the potential to provide a dual-action strategy by both directly targeting cancer cells and enhancing the immune response, which could lead to more effective and sustained results for patients.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research shows that using regorafenib and pembrolizumab together may help treat advanced liver cancer. This trial will investigate the combination of regorafenib and pembrolizumab for patients with advanced liver cancer, also known as hepatocellular carcinoma (HCC). Early results from other studies suggest that these drugs might offer long-term benefits in fighting liver cancer. Regorafenib stops cancer cells from growing, while pembrolizumab, an immunotherapy, helps the body attack cancer cells. Together, they enhance treatment effects. These findings suggest that this combination could be a promising option for treating liver cancer. Meanwhile, another arm of this trial will compare the effectiveness of loco-regional therapy, such as TACE, as a control treatment. ^{1 2 4 6 7}

Who Is on the Research Team?

Peter R Galle, MD

Principal Investigator

University Medical Center, Mainz, Germany

Richard S Finn, MD

Principal Investigator

UCLA Department of Medicine, Division of Hematology-Oncology

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

No evidence of MVI or EHS

My liver cancer is at an intermediate stage.

My blood counts and organ functions are within normal ranges.

Exclusion Criteria

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

My heart condition fits the study's specific requirements.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Regorafenib in combination with Pembrolizumab or TACE/TARE until progressive disease or unacceptable toxicity

up to 3.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 3.5 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Regorafenib
• Transarterial Chemoembolization (TACE)

Trial Overview 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.

How Is the Trial Designed?

Group I: Regorafenib + Pembrolizumab Experimental Treatment 1 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 therapy Active Control 1 Intervention

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

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Translational Research in Oncology

Lead Sponsor

Trials

22

Recruited

6,700+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Published Research Related to This Trial

In a study of 76 colorectal cancer liver metastases patients, combining regorafenib with drug-eluting beads-transarterial chemoembolization (DEB-TACE) significantly improved treatment response rates, with an objective response rate of 35.3% compared to 7.1% for regorafenib alone.

Patients receiving the combination therapy also experienced longer progression-free survival (7.6 months vs. 4.1 months) and overall survival (15.7 months vs. 9.2 months), although they reported more mild and tolerable side effects like abdominal pain and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization versus regorafenib monotherapy in colorectal cancer liver metastasis patients who fail standard treatment regimens. Cao, F., Zheng, J., Luo, J., et al.[2022]

In a study of 59 patients with advanced hepatocellular carcinoma (HCC) who had failed first-line treatment, regorafenib combined with transcatheter arterial chemoembolization (TACE) resulted in an objective response rate (ORR) of 42.3% and a disease control rate (DCR) of 66.1%, indicating significant efficacy in this patient population.

The treatment was generally safe, with most adverse events being manageable; only 9 patients experienced severe (grade 3 or 4) reactions, and there were no treatment-related deaths, suggesting that regorafenib combined with TACE is a viable option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study on safety and efficacy of regorafenib combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma after first-line targeted therapy. Wang, H., Xiao, W., Han, Y., et al.[2022]

In a multicenter study involving patients with unresectable hepatocellular carcinoma (HCC) who had failed first-line treatments, the combination of transarterial chemoembolization (TACE) and regorafenib showed a median overall survival of 14.3 months, indicating its potential effectiveness as a second-line therapy.

The treatment was generally well-tolerated, with a low incidence of severe adverse events (15.8%), suggesting that this combination therapy could be a safe option for patients with advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib combined with transarterial chemoembolization for unresectable hepatocellular carcinoma: a real-world study. Han, Y., Cao, G., Sun, B., et al.[2022]

In a study of 52 patients with advanced hepatocellular carcinoma, the combination of regorafenib plus immune checkpoint inhibitors and transarterial chemoembolization (R+ICIs+TACE) resulted in a significantly higher objective response rate (34.8% vs 4.3%) and improved progression-free survival (5.8 months vs 2.6 months) compared to regorafenib plus ICIs alone.

Patients receiving R+ICIs+TACE also experienced longer overall survival (15.0 months vs 7.5 months) without a significant increase in treatment-related adverse events, indicating that this combination therapy is both effective and safe for second-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Regorafenib Plus Immune Checkpoint Inhibitors with or Without TACE as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis. Yang, X., Deng, H., Sun, Y., et al.[2023]

Regorafenib is an effective oral tyrosine kinase inhibitor approved for treating refractory metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and unresectable hepatocellular carcinoma, with its efficacy supported by phase 3 trials like CORRECT, CONCUR, GRID, and RESORCE.

The review highlights the need for managing drug-related toxicities through dose optimization and emphasizes ongoing research into biomarkers that could predict patient responses to regorafenib, as well as its potential effectiveness in other cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of regorafenib for the treatment of advanced cancers. Grothey, A., Blay, JY., Pavlakis, N., et al.[2020]

Regorafenib is an effective oral multikinase inhibitor approved by the FDA for treating metastatic colorectal cancer in patients who have not responded to standard chemotherapy and other targeted therapies, showing significant efficacy compared to placebo in the CORRECT trial.

While regorafenib has a greater antiangiogenic effect than sorafenib, it is associated with common severe side effects such as hand-foot skin reactions, diarrhea, hypertension, and fatigue, which require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of regorafenib-related toxicities: a review. Krishnamoorthy, SK., Relias, V., Sebastian, S., et al.[2022]

Regorafenib is an oral multikinase inhibitor approved for treating pretreated metastatic colorectal cancer and gastrointestinal stromal tumors, showing antiangiogenic and antiproliferative effects, based on data from phase III studies.

Currently, regorafenib is being investigated in phase III trials for hepatocellular carcinoma and in several phase II studies for other gastrointestinal tumors, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. Rey, JB., Launay-Vacher, V., Tournigand, C.[2021]

In a study involving patients with advanced hepatocellular carcinoma (HCC) who had previously failed second-line treatment with regorafenib, the combination of transcatheter arterial chemoembolization (TACE) with regorafenib and PD-1 antibody showed a higher disease-control rate (DCR) of 88.9% compared to 55.6% for continued TACE with regorafenib.

While the combination treatment was more effective, it also posed a risk of severe immune responses, which could potentially increase the risk of death, leading some patients to prefer the continued TACE with regorafenib despite similar overall response rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study on efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with regorafenib and PD-1 antibody versus continued TACE combined with regorafenib in patients with hepatocellular carcinoma after failed second-line treatment with regorafenib. Wang, H., Xiao, W., Han, Y., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12478257/

Randomized phase II study comparing two doses of ... Regorafenib was safely administered at 160 mg/day and 80 mg/day, and an exploratory efficacy analysis found no significant difference between ...

2. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/55/NCT04696055/Prot_000.pdf

Study Protocol Study Phase: 2. Short Title: Pilot study of regorafenib plus pembrolizumab in advanced HCC patients who have been previously treated with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9534176/

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4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/55/NCT04696055/SAP_001.pdf

Document Type: Statistical Analysis Plan Official Title This clinical study aims to evaluate the efficacy and safety of regorafenib in combination with pembrolizumab for the treatment of advanced Hepatocellular ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT322531

Results of a phase Ib study of regorafenib (REG) 80 mg/ ... Results of a phase Ib study of regorafenib (REG) 80 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03347292

Regorafenib Plus Pembrolizumab in First Line Systemic ... This study will determine if the combination of regorafenib and pembrolizumab is safe and tolerated in patients with advanced liver cancer.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1567576922008852

Immunotherapy combination with regorafenib for refractory ... Immunotherapy plus regorafenib may significantly improve clinical outcomes and have a manageable safety profile compared with regorafenib monotherapy in ...