Immunotherapy + TACE +/- Lenvatinib for Liver Cancer

(EMERALD-3 Trial)

Recruiting at 157 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

760 Participants Needed

Trial Summary

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.

What data supports the idea that Immunotherapy + TACE +/- Lenvatinib for Liver Cancer is an effective treatment?

The available research shows that the combination of tremelimumab and durvalumab, which are part of the immunotherapy treatment, has been approved for treating liver cancer. In a study called HIMALAYA, this combination was shown to help patients live longer compared to another drug called sorafenib. Specifically, patients lived for about 16.4 months on average with the combination treatment, compared to 13.8 months with sorafenib. This suggests that the immunotherapy combination is more effective than some existing treatments for liver cancer. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination of Durvalumab and Tremelimumab for liver cancer?

The combination of Durvalumab and Tremelimumab has been shown to improve overall survival in patients with unresectable hepatocellular carcinoma (a type of liver cancer) compared to the drug sorafenib, as demonstrated in the HIMALAYA study. This combination was approved by the FDA based on these results, indicating its effectiveness in treating this type of liver cancer. ^{1 2 3 4 5}

What safety data exists for the treatment of liver cancer with Immunotherapy + TACE +/- Lenvatinib?

The provided research does not contain relevant safety data for the treatment of liver cancer with Immunotherapy + TACE +/- Lenvatinib. The studies focus on the safety and efficacy of teriflunomide and other treatments for multiple sclerosis, not the treatments in question for liver cancer. ^{6 7 8 9 10}

Is the drug combination of Durvalumab, Lenvatinib, and Tremelimumab promising for liver cancer?

Yes, the combination of these drugs shows promise for treating liver cancer. Studies suggest that using Lenvatinib with other treatments like Durvalumab and Tremelimumab can be effective, especially for cases where surgery isn't an option. This combination may improve the treatment's effectiveness against the cancer. ^{11 12 13 14 15}

How is the treatment with Durvalumab, Lenvatinib, and Tremelimumab for liver cancer different from other treatments?

This treatment combines immunotherapy (using the body's immune system to fight cancer) with a drug called Lenvatinib and a procedure called TACE (which blocks blood supply to the tumor), offering a unique approach for liver cancer that cannot be removed by surgery. It is different because it combines multiple methods to potentially enhance effectiveness against the cancer. ^{11 12 13 14 15}

What is the purpose of this trial?

A global study to evaluate transarterial chemoembolization (TACE) in combination with durvalumab, tremelimumab and lenvatinib therapy in patients with locoregional hepatocellular carcinoma

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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 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]

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 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Teriflunomide. [2021]

7. Russia (Federation) 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]. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study. [2021]

9. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Tolerability and discontinuation rates in teriflunomide-treated patients. A real-world clinical experience. [2021]

10. England 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. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma. [2023]

14. Germany pubmed.ncbi.nlm.nih.gov

The combination treatment strategy of lenvatinib for hepatocellular carcinoma: a real-world study. [2023]

15. Switzerland 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. [2022]