Immunotherapy + TACE +/- Lenvatinib for Liver Cancer

(EMERALD-3 Trial)

Not currently recruiting at 198 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Disqualifiers: Congestive heart failure, Angina, Arrhythmia, Hypertension, 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: Approximately 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of treatments to determine if they work better together for individuals with liver cancer confined to the liver. It examines the use of transarterial chemoembolization (TACE), a procedure that delivers chemotherapy directly to the liver, alongside the immunotherapy drugs durvalumab, tremelimumab, and sometimes lenvatinib, a targeted therapy drug. The trial includes three groups: one receives all three drugs with TACE, another receives two drugs with TACE, and the third receives only TACE. Suitable candidates have liver cancer that cannot be cured with surgery but may be treated with TACE, and they do not have liver disease affecting other parts of the body. As a Phase 3 trial, this study represents the final step before FDA approval, providing access to potentially effective treatments.

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

The trial information does not specify if you need to stop taking your current medications. Please consult with the trial coordinators for more details.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that combining tremelimumab, durvalumab, and lenvatinib with transarterial chemoembolization (TACE) is generally well-tolerated by patients with liver cancer. Earlier studies found that patients treated with tremelimumab and durvalumab experienced benefits without major safety issues. These treatments, when used together, had a manageable safety profile.

Side effects occurred, but most were mild to moderate. Common side effects included tiredness and nausea. Lenvatinib has been used for liver cancer before, and its safety is well-known. Most side effects of lenvatinib were mild, such as high blood pressure and loss of appetite.

Overall, the combination treatments in this study have demonstrated a promising safety record, making them a reasonable option for those considering participation in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of immunotherapy and TACE for liver cancer because it brings a fresh approach to treatment. Unlike traditional therapies like sorafenib, which mainly target cancer cells directly, this combination employs the body's immune system to fight the cancer. Durvalumab and Tremelimumab are immunotherapy agents that help the immune system recognize and attack cancer cells. Lenvatinib, when used in one of the treatment arms, adds another layer by inhibiting tumor blood vessel growth, potentially enhancing the immune response. This multi-pronged strategy could offer more effective results compared to current standard treatments.

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

Research shows that combining tremelimumab and durvalumab with TACE, a procedure that cuts off the tumor's blood supply, benefits liver cancer patients. In this trial, some participants will receive this combination. Studies indicate this combination effectively treats liver cancer that cannot be removed by surgery, leading to better patient outcomes. Another arm of this trial will explore adding lenvatinib to tremelimumab, durvalumab, and TACE. Evidence suggests that lenvatinib, a drug that helps patients live longer, could enhance this treatment's effectiveness. Early results from past trials suggest high success rates with these immune checkpoint inhibitors, which help the body's immune system fight cancer more effectively. Overall, these combinations show promise for improving treatment results in liver cancer patients. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for adults with hepatocellular carcinoma (a type of liver cancer) that can't be removed by surgery but can be treated with TACE. Participants should have no cancer outside the liver, an ECOG performance status of 0 or 1 indicating they are fully active or restricted in physically strenuous activity only, and a Child Pugh score class A showing mild liver disease.

Inclusion Criteria

My cancer has not spread outside my liver.

My liver function is good.

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

Exclusion Criteria

I have had serious heart problems like heart failure, chest pain, or irregular heartbeat.

I am co-infected with both Hepatitis B and D.

Major portal vein thrombosis visible on baseline imaging

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tremelimumab, Durvalumab, and Lenvatinib in combination with Transarterial Chemoembolization (TACE) or TACE alone

Approximately 5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Lenvatinib
• Transarterial Chemoembolization (TACE)
• Tremelimumab

Trial Overview The study tests if combining TACE with durvalumab and tremelimumab, with or without lenvatinib, improves outcomes in patients with locoregional HCC. It's a global study assessing the effectiveness and safety of these therapies when used together.

How Is the Trial Designed?

Group I: Arm B Experimental Treatment 3 Interventions

Tremelimumab and Durvalumab in combination with Transarterial Chemoemobolization (TACE)

Group II: Arm A Experimental Treatment 4 Interventions

Tremelimumab, Durvalumab and Lenvatinib in combination with Transarterial Chemoembolization (TACE)

Group III: Arm C Active Control 1 Intervention

Transarterial Chemoembolization (TACE)

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?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

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]

Since the approval of sorafenib in 2007, multiple new treatments for unresectable hepatocellular carcinoma have emerged, including lenvatinib and the combination of atezolizumab plus bevacizumab, enhancing options for patients.

Recent studies presented at the 2022 ASCO Gastrointestinal Cancers Symposium indicate that the combination of durvalumab and tremelimumab may significantly improve overall survival compared to sorafenib, marking a potential shift in treatment strategies for both advanced and intermediate-stage hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma. Kudo, M.[2023]

In a study of 118 patients with unresectable hepatocellular carcinoma (HCC), triple therapy combining lenvatinib, a PD-1 inhibitor, and transarterial chemoembolization (TACE) significantly improved overall survival (29.0 months vs. 17.8 months) and progression-free survival (16.2 months vs. 10.2 months) compared to dual therapy with lenvatinib and PD-1 inhibitor.

The triple therapy also resulted in higher objective response rates (76.7% vs. 44.9%) and disease control rates (96.7% vs. 75.9%) without increasing the incidence or severity of adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma. Xin, Y., Zhang, X., Liu, N., et al.[2023]

In a study of 215 patients with unresectable hepatocellular carcinoma (HCC), combination therapies involving lenvatinib significantly improved progression-free survival (PFS) compared to lenvatinib alone, with PFS of 7.77 months versus 4.43 months.

The combination therapies also resulted in a higher objective response rate (ORR), with 37% of patients responding compared to only 5% in the monotherapy group, although these combinations were associated with more adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination treatment strategy of lenvatinib for hepatocellular carcinoma: a real-world study. Chen, J., Xiong, P., Nie, M., et al.[2023]

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]

In a study of 53 patients with advanced hepatocellular carcinoma (HCC) who received lenvatinib after immunotherapy, the median overall survival was 12.8 months, indicating that lenvatinib can be an effective second-line treatment following immunotherapy failure.

The median progression-free survival was 3.7 months, suggesting that while lenvatinib provides some benefit, the optimal treatment sequence after immunotherapy for advanced HCC still needs further investigation through clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study. Palmer, ME., Gile, JJ., Storandt, MH., et al.[2023]

In a study of 247 patients with unresectable hepatocellular carcinoma, LEN-TACE sequential therapy showed significantly better overall survival and progression-free survival compared to LEN monotherapy, indicating its enhanced efficacy.

The objective response rate for LEN-TACE was 61.9%, and the study found that a positive initial response to LEN treatment was a key factor in achieving a deep response during sequential therapy, suggesting that prior treatment response can guide future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Objective Response by mRECIST to Initial Lenvatinib Therapy Is an Independent Factor Contributing to Deep Response in Hepatocellular Carcinoma Treated with Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy. Kuroda, H., Oikawa, T., Ninomiya, M., et al.[2022]

The FDA approved tremelimumab in combination with durvalumab for treating unresectable hepatocellular carcinoma based on the HIMALAYA study, which showed a significant improvement in overall survival (OS) compared to sorafenib, with a median OS of 16.4 months versus 13.8 months.

Common adverse reactions in patients receiving the combination treatment included rash, fatigue, diarrhea, and abdominal pain, occurring in 20% or more of patients, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. Patel, TH., Brewer, JR., Fan, J., et al.[2023]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

Teriflunomide is an effective oral treatment for multiple sclerosis (MS), showing clinical efficacy and safety in large phase III clinical trials.

The drug benefits from existing safety data from its parent compound, leflunomide, which supports its long-term safety profile in MS treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Teriflunomide. Oh, J., O'Connor, PW.[2021]

In a study involving 618 patients with clinically isolated syndrome, teriflunomide significantly reduced the risk of relapse leading to clinically definite multiple sclerosis compared to placebo, with hazard ratios of 0.574 for the 14 mg dose and 0.628 for the 7 mg dose.

Teriflunomide also decreased the risk of relapse or new MRI lesions, demonstrating its efficacy as an oral disease-modifying therapy for early multiple sclerosis, although some patients experienced increased liver enzymes and hair thinning as common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Miller, AE., Wolinsky, JS., Kappos, L., et al.[2022]

In a study of 62 patients with unresectable hepatocellular carcinoma (uHCC), the combination of lenvatinib, anti-PD-1 antibodies, and transcatheter arterial chemoembolization (TACE) resulted in a high objective response rate of approximately 80%, indicating strong efficacy in shrinking tumors.

Over half of the patients (53.2%) became eligible for surgical resection after treatment, demonstrating the potential of this triple therapy to convert previously unresectable tumors into resectable ones, with manageable side effects reported in 74.2% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. Wu, JY., Yin, ZY., Bai, YN., et al.[2022]

In a 52-week randomized study followed by an additional 48 weeks of open-label treatment, teberif (a biosimilar of interferon β-1a) demonstrated equivalent efficacy to rebif in patients with relapsing multiple sclerosis, confirming its effectiveness over a total of 2 years.

The safety and tolerability profiles of teberif were comparable to rebif, and switching from rebif to teberif did not affect treatment efficacy, indicating that teberif is a safe alternative for patients previously on rebif.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy, tolerability and safety of the treatment with teberif: the results of a 2-year randomized clinical trial of treatment naïve patients with remitting multiple sclerosis, who have not received DMT, after switching from other interferon β-1a]. Boyko, AN., Bosenko, LP., Vasilovskiy, VV., et al.[2019]

In a study of 2,236 patients with relapsing-remitting multiple sclerosis, dimethyl fumarate (DMF) showed a significantly lower annualized relapse rate (0.09) compared to teriflunomide (TFL) (0.16), indicating better efficacy in preventing relapses.

DMF also had a higher proportion of patients remaining relapse-free after 48 months and a lower rate of discontinuation due to disease breakthrough (10.2% for DMF vs. 22.1% for TFL), suggesting it may be a more favorable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study. Buron, MD., Chalmer, TA., Sellebjerg, F., et al.[2021]

In a study of 119 multiple sclerosis patients, teriflunomide was found to have a low discontinuation rate of 15.9% after an average of 35 weeks, primarily due to side effects.

There was no significant difference in tolerability between treatment-naive and previously treated patients, suggesting that teriflunomide is a safe and well-tolerated oral alternative to injectable therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and discontinuation rates in teriflunomide-treated patients. A real-world clinical experience. Alnajashi, HA., Alshamrani, FJ., Freedman, MS.[2021]

Citations

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2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK599983/

Tremelimumab (Imjudo) in Combination With Durvalumab ... ... tremelimumab in combination with durvalumab resulted in added clinical benefit in adult patients with unresectable hepatocellular carcinoma. The HIMALAYA ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)02702-8/fulltext

EMERALD-3 Lenvatinib improved survival outcomes vs TACE in patients with unresectable HCC in a proof of concept study (Kudo et al. Cancers [Basel] 2019;11:1804). EMERALD- ...

4. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D910VC00001

Evaluate Durvalumab and Tremelimumab +/- Lenvatinib in ... A global study to evaluate transarterial chemoembolization (TACE) in combination with durvalumab, tremelimumab and lenvatinib therapy in patients with ...

5. canjhealthtechnol.ca canjhealthtechnol.ca/index.php/cjht/article/view/PC0308r/1770

Tremelimumab (Imjudo) in Combination With Durvalumab ... The durvalumab product monograph will be updated to reflect the unresectable hepatocellular carcinoma indication via a supplement to a new drug submission ...

6. cda-amc.ca cda-amc.ca/sites/default/files/DRR/2023/PC0308-Imfinzi-and-Imjudo-Combined-Report.pdf

Tremelimumab (Imjudo) in Combination With Durvalumab ( ... Lenvatinib (lenvima) for hepatocellular carcinoma. pCODR final economic guidance report. Ottawa (ON): CADTH; 2019: https:// www .cadth .ca ...