Regorafenib + Durvalumab for Liver Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Overseen byMehmet Akce
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Academic and Community Cancer Research United
Must not be taking: Immunosuppressants, Antiretrovirals
Disqualifiers: Autoimmune disorders, Uncontrolled hypertension, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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 of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving regorafenib and durvalumab may work better in treating patients with high-risk liver cancer.
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.
What data supports the effectiveness of the drug combination Regorafenib and Durvalumab for liver cancer?
Regorafenib has shown significant improvement in progression-free survival and overall survival in patients with advanced hepatocellular carcinoma (a type of liver cancer) previously treated with Sorafenib. Durvalumab, as an immune checkpoint inhibitor, has demonstrated prolonged survival benefits in advanced hepatocellular carcinoma and other cancers.
12345What safety information is available for Regorafenib and Durvalumab in humans?
Regorafenib has been studied in various cancers and is generally considered safe, with common side effects including hand-foot skin reaction, fatigue, diarrhea, and high blood pressure. These side effects are often mild to moderate and can be managed with dose adjustments and supportive care.
46789How is the drug combination of Regorafenib and Durvalumab unique for liver cancer?
The combination of Regorafenib and Durvalumab is unique for liver cancer because it combines a multi-kinase inhibitor (Regorafenib) that targets various cancer growth pathways with an immune checkpoint inhibitor (Durvalumab) that helps the immune system attack cancer cells, offering a novel approach compared to standard treatments.
410111213Eligibility Criteria
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.
+23 more
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.
I have a skin condition that doesn't need treatment with pills or injections.
+31 more
Trial Timeline
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (regorafenib, durvalumab)Experimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Alabama - BirminghamBirmingham, AL
University of Alabama at Birmingham Cancer CenterBirmingham, AL
Emory University Hospital/Winship Cancer InstituteAtlanta, GA
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Who Is Running the Clinical Trial?
Academic and Community Cancer Research UnitedLead Sponsor
National Cancer Institute (NCI)Collaborator
References
A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.
Durvalumab in non-small-cell lung cancer patients: current developments. [2018]Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy. Impressive activity has been recently reported after chemoradiation in locally advanced patients; promising activity was observed with other ICI combinations, and potentially with other drugs including platinum-based chemotherapy. In contrast, early data reveal lower response rates in EGFR and ALK-positive patients.
Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.
Regorafenib. [2018]Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multi-kinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multi-kinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, Regorafenib was FDA approved for this indication in 2012. In addition, Regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared to placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also FDA-approved in this indication since 2013. In 2017, Regorafenib has been FDA approved for the treatment of patients with advanced hepatocellular carcinoma (HCC) previously treated with Sorafenib. In this situation, Regorafenib significantly improved PFS and overall survival (OS) compared to placebo. Regorafenib has also been examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), soft-tissue sarcoma (STS), and additional phase II trials ongoing (e.g., second- and third-line treatment for medullary thyroid cancer, NCT02657551).
Durvalumab: First Global Approval. [2022]Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ± tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma.
[Regorafenib approved in Metastatic Colorectal cancer]. [2022]Regorafenib, oral multi-kinase inhibitor that targets oncogenesis, tumor angiogenesis and maintenance of the tumor microenvironment, obtained its European approval, August 26, 2013 after favorable review of the European Medecines Agency in the following indication: treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy or are not considered candidates for available therapies and, if KRAS wild type, an anti-EGFR therapy. This decision was based on the efficacy and safety results of an international phase III trial. This study showed an improved overall survival, with régorafénib versus placebo (6.4 months vs 4 months; HR = 0.774, IC à 95%, 0.64 à 0.94; p = 0,005 2). Reported grade 3-4 adverse events with regorafenib were hand-foot syndrome (17%), asthenia (10%), diarrhea (7%), hypertension (7%), rash and desquamation (6%).
Regorafenib: A Review in Hepatocellular Carcinoma. [2022]Regorafenib (Stivarga®), a small molecule inhibitor of multiple kinases, is the first drug to be approved for the treatment of hepatocellular carcinoma (HCC) in patients who have progressed during or after sorafenib therapy. Its approval was based on the results of the randomized, double-blind, placebo-controlled, multinational, phase III RESORCE trial in patients with HCC who had progressed during sorafenib therapy. In RESORCE, regorafenib significantly prolonged overall survival (OS; primary endpoint), progression-free survival (PFS) and time to progression (TTP) compared with placebo, with the OS benefit appearing to be largely due to disease stabilization. Regorafenib had an acceptable tolerability profile. The most common treatment-related adverse events in the regorafenib group included hand-foot skin reaction, fatigue, diarrhoea and hypertension. No fatal hepatic failure was reported with regorafenib in patients with HCC in RESORCE. In conclusion, current evidence suggests that regorafenib is an important new targeted therapy option for the treatment of HCC patients who have progressed on sorafenib therapy.
Regorafenib: A Review in Metastatic Colorectal Cancer. [2019]Regorafenib (Stivarga®) is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC). In the EU and USA it is indicated for patients with mCRC who have been previously treated with, or are not considered candidates for available therapies, including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy. In Japan, it is indicated for the treatment of unresectable, advanced/recurrent CRC. The addition of regorafenib to best supportive care prolonged median overall survival (OS; by up to 2.5 months) and progression-free survival (PFS; by up to 1.5 months) relative to the addition of placebo in double-blind phase 3 studies (CORRECT and CONCUR) in patients with mCRC who had progressed after failure of standard therapy. Health-related quality of life was not adversely affected with regorafenib relative to placebo. A large open-label phase 3 study (CONSIGN) and several large real-world studies supported the efficacy of regorafenib in this setting. Regorafenib had a generally manageable tolerability profile, which was consistent with the profile of a typical small-molecule multiple kinase inhibitor. Treatment-related adverse events (AEs), mostly of mild or moderate severity, were reported in the majority of patients receiving regorafenib, with dermatological toxicities and liver enzyme elevations among the most common AEs. Although identification of biomarkers/parameters predicting efficacy outcomes with regorafenib will help to individualize therapy, current evidence indicates that regorafenib is a valuable treatment option for patients with refractory mCRC who have a very poor prognosis.
Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. [2015]Regorafenib is the first tyrosine kinase inhibitor approved for metastatic colorectal cancer. In 2 phase III trials, regorafenib significantly improved progression-free and overall survival in patients who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if (K)RAS wild type, an anti-epidermal growth factor receptor therapy. Its safety profile is in line with other multikinase and/or tyrosine kinase inhibitors approved for different indications. Commonly reported adverse events specifically associated with regorafenib include hand-foot skin reaction and hypertension, whereas others such as fatigue, diarrhea, and liver dysfunction may occur during both targeted and cytotoxic treatments. These adverse events frequently occur within the first cycles of treatment, are transient, and decrease in incidence over time. Patient selection, education, and management, as well as close communication between oncologists or trained nurses and patients, are essential for prevention and mitigation of treatment toxicity as is rapid implementation of dose modifications and temporary discontinuations. Effective management of adverse events enables patients who are responding to stay on treatment for a substantial period of time and thereby receive the full benefit of regorafenib therapy. This review aims to provide guidance around prophylaxis and management of regorafenib-associated adverse events.
Sequential therapy including regorafenib for unresectable hepatocellular carcinoma: Effect of early relative changes in hepatic functional reserve after regorafenib administration on prognosis. [2021]Regorafenib is a second-line treatment for unresectable hepatocellular carcinoma after sorafenib-refractory treatment. This study examined the effects of regorafenib administration on hepatic functional reserve and the treatment course after regorafenib discontinuation.
Toxicity and early outcomes of regorafenib in multiply pre-treated metastatic colorectal adenocarcinoma-experience from a tertiary cancer centre in India. [2022]Regorafenib is a multikinase inhibitor (MKI) approved for use in multiply pre-treated metastatic colorectal cancers (mCRC). To the best of our knowledge, this is the first report of regorafenib from India.
Regorafenib in previously treated advanced hepatocellular carcinoma: Impact of prior immunotherapy and adverse events. [2021]Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary.
Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China. [2022]Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear.