Regorafenib + Durvalumab for Liver Cancer

Not currently recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Autoimmune disorders, Uncontrolled hypertension, others

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

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 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining regorafenib and durvalumab can effectively shrink tumors in people with high-risk liver cancer. Regorafenib blocks enzymes that aid tumor growth, while durvalumab, an immunotherapy, helps the immune system fight cancer. This trial may suit individuals with hepatocellular carcinoma (a type of liver cancer) who haven't received certain cancer treatments and don't have additional liver conditions. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot take any other cancer treatments or immunosuppressive medications while participating in this study.

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

Research has shown that the combination of regorafenib and durvalumab is generally well-tolerated. A study on regorafenib for liver cancer found that its side effects are predictable and manageable. Common side effects include tiredness and high blood pressure, which can usually be controlled with proper care.

Real-world studies have confirmed the safety of regorafenib in a wide range of liver cancer patients. Another study examined regorafenib combined with immune system drugs like durvalumab, showing improved safety and better results.

Overall, past patients demonstrated that these treatments can be safe options, with side effects manageable under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of regorafenib and durvalumab for liver cancer because it offers a new way to tackle the disease. Unlike standard treatments like sorafenib, which mainly target cancer growth through inhibiting certain proteins, this combination adds durvalumab, an immunotherapy drug that stimulates the immune system to attack cancer cells. Regorafenib also targets multiple proteins involved in tumor growth, enhancing its effectiveness. Together, they provide a dual approach: blocking tumor growth and boosting the body’s natural defenses, which could lead to better outcomes for patients.

What evidence suggests that regorafenib and durvalumab might be effective treatments for liver cancer?

Research has shown that regorafenib effectively treats liver cancer. The REFINE study found it works well for many patients with liver cancer, also known as hepatocellular carcinoma (HCC). Another study found that patients using regorafenib lived more than two years longer after previous treatments. Durvalumab, an immunotherapy, helps the immune system attack cancer cells more effectively. In this trial, participants will receive a combination of regorafenib and durvalumab. This combination is promising because regorafenib stops tumor growth, while durvalumab strengthens the body's natural defenses. Early research suggests this combination may shrink tumors in patients with high-risk liver cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Mehmet Akce

Principal Investigator

Academic and Community Cancer Research United

Are You a Good Fit for This Trial?

Adults with high-risk liver cancer (Hepatocellular Carcinoma) who can swallow pills, have no severe liver issues (Child Pugh class A), and are not pregnant. They should be able to follow the study protocol and haven't had certain treatments for liver cancer or immunotherapies like Durvalumab before.

Inclusion Criteria

Urinary protein is =< 1+ on dipstick or routine urinalysis or 24-hour urine demonstrating < 1 gram of protein (obtained =< 28 days prior to registration)

I can take pills by mouth.

My liver cancer is at an early to mid-stage according to the AJCC 8th edition.

Exclusion Criteria

My early-stage cancer was treated successfully with no current signs of it.

I haven't had active disease in the last 5 years and have consulted the study doctor.

History of allogenic organ transplantation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive regorafenib orally once daily on days 1-21 and durvalumab intravenously on day 1. Treatment repeats every 28 days for a maximum of 2 years or until decision to proceed to surgery, disease progression, excessive toxicity, or patient withdrawal.

Up to 2 years

Follow-up

Participants are monitored every 90 days for safety and effectiveness after treatment completion

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Regorafenib

Trial Overview The trial is testing a combination of Regorafenib, which blocks enzymes needed for tumor growth, and Durvalumab, an antibody that helps the immune system fight cancer. It aims to see if this combo is better at shrinking tumors in patients with advanced liver cancer.

How Is the Trial Designed?

Group I: Treatment (regorafenib, durvalumab) Experimental Treatment 2 Interventions

Patients receive regorafenib PO QD on days 1-21 and durvalumab IV on day 1. Treatment repeats every 28 days for a maximum of 2 years from registration or until decision to proceed to surgery, disease progression, excessive toxicity, or patient withdrawal.

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 23 patients with metastatic colorectal cancer who had previously undergone multiple treatments, regorafenib showed some efficacy, with 34.8% achieving stable disease and 8.7% showing partial response, although 56.5% experienced disease progression.

Regorafenib treatment was associated with significant side effects, with 65% of patients experiencing severe toxicity, primarily hand-foot syndrome and fatigue, leading to dose reductions in 86.9% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and early outcomes of regorafenib in multiply pre-treated metastatic colorectal adenocarcinoma-experience from a tertiary cancer centre in India. Zanwar, S., Ostwal, V., Gupta, S., et al.[2022]

Regorafenib is the first approved tyrosine kinase inhibitor for metastatic colorectal cancer, showing significant improvements in progression-free and overall survival in patients who had previously undergone multiple lines of chemotherapy and targeted therapies, based on results from two phase III trials.

While regorafenib has a safety profile similar to other tyrosine kinase inhibitors, it is associated with specific adverse events like hand-foot skin reaction and hypertension, which can be managed effectively through patient education and timely dose adjustments, allowing patients to continue benefiting from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Hofheinz, RD., Arnold, D., Kubicka, S., et al.[2015]

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

Regorafenib is the first approved treatment for hepatocellular carcinoma (HCC) in patients who have not responded to sorafenib, showing significant improvements in overall survival and disease stabilization in the phase III RESORCE trial.

The drug has a manageable safety profile, with common side effects including hand-foot skin reactions and fatigue, and importantly, no cases of fatal hepatic failure were reported during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Hepatocellular Carcinoma. Heo, YA., Syed, YY.[2022]

In a study of 51 patients with unresectable hepatocellular carcinoma (u-HCC) treated with regorafenib after failing sorafenib, the median survival time was 16.7 months, indicating that regorafenib can be an effective second-line treatment.

The study found that maintaining a favorable hepatic functional reserve during regorafenib treatment is crucial for improving prognosis, with patients who had better liver function before and during treatment experiencing significantly longer survival times.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis. Ochi, H., Tani, J., Tomonari, T., et al.[2021]

In a study of 43 advanced hepatocellular carcinoma (HCC) patients receiving sequential therapy with sorafenib followed by regorafenib, the median progression-free survival (PFS) was 11 months and median overall survival (OS) was 17 months, indicating that this treatment approach is effective after sorafenib failure.

The treatment was generally well-tolerated, with common side effects including hand-foot skin reactions and diarrhea, and specific pre-treatment factors like high alpha-fetoprotein (AFP) levels were associated with better PFS outcomes, suggesting that patient selection may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China. Ren, SH., Cui, ZL., Lang, MR., et al.[2022]

Regorafenib significantly improves overall survival by up to 2.5 months and progression-free survival by up to 1.5 months in patients with metastatic colorectal cancer (mCRC) who have not responded to standard therapies, based on phase 3 studies.

The treatment is generally well-tolerated, with most side effects being mild to moderate, and it does not negatively impact health-related quality of life compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib: A Review in Metastatic Colorectal Cancer. Dhillon, S.[2019]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Regorafenib is an effective treatment for patients with metastatic colorectal cancer who have previously undergone multiple chemotherapy regimens, showing a significant improvement in overall survival compared to placebo (6.4 months vs 4 months).

The treatment is associated with manageable side effects, with the most common severe adverse events being hand-foot syndrome (17%) and asthenia (10%), indicating that while it is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regorafenib approved in Metastatic Colorectal cancer]. André, T., Dumont, SN.[2022]

The DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

In a study of 440 patients with unresectable hepatocellular carcinoma (uHCC) who received regorafenib after prior treatment with sorafenib, the overall survival (OS) was found to be 12.1 months, indicating that regorafenib is effective in real-life clinical settings.

The occurrence of hand-foot skin reaction (HFSR) during treatment with regorafenib was significantly associated with improved overall survival, suggesting that this side effect may serve as a positive prognostic indicator.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events. Yoo, C., Byeon, S., Bang, Y., et al.[2021]

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05194293

NCT05194293 | Regorafenib and Durvalumab for the ... This phase II trial tests whether regorafenib and durvalumab work to shrink tumors in patients with high-risk liver cancer. Regorafenib may stop the growth ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12360744/

Regorafenib for Hepatocellular Carcinoma in Real-World ... The results of the real-world REFINE study confirmed the safety and effectiveness of regorafenib in a broad population of patients with uHCC. Of patients who ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT434862

Phase I/II clinical trial of regorafenib plus durvalumab ... Furthermore, single agent regorafenib has exhibited efficacy in patients with refractory advanced metastatic cholangiocarcinoma, particularly in terms of ...

4. stivarga.com stivarga.com/hcc/efficacy

Efficacy Data in Hepatocellular Carcinoma A RESORCE retrospective analysis showed a >2 year survival benefit in patients taking STIVARGA after treatment with NEXAVAR.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7364795/

Efficacy and safety of regorafenib as beyond second-line ... This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC.

6. stivarga.com stivarga.com/hcc/safety

Safety Data in Hepatocellular Carcinoma STIVARGA® (regorafenib) has a predictable and manageable safety profile1 · Drug-related, treatment-emergent AEs occurring in ≥5% of patients2 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11231837/

Efficacy and safety of regorafenib as a first-line agent alone or ... Regorafenib, alone or combined with immune checkpoint inhibitors (ICIs), demonstrates enhanced efficacy and survival in treating advanced hepatocellular ...