Durvalumab + Tremelimumab for Liver Cancer

(SIERRA Trial)

Not currently recruiting at 53 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: Antivirals

Must not be taking: Immunosuppressants, Torsades de Pointes

Disqualifiers: Heart failure, Autoimmune disorders, HIV, 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 33 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates whether a combination of two drugs, Durvalumab and Tremelimumab, is safe and effective as an initial treatment for individuals with advanced liver cancer that cannot be surgically removed. The trial targets those with hepatocellular carcinoma (HCC) who have not received other treatments and have a measurable tumor. Ideal candidates are those whose liver cancer cannot be treated with local therapies and who meet specific health criteria, such as not having severe immune system issues. As a Phase 3 trial, this study represents the final step before FDA approval, providing patients an opportunity to access potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use immunosuppressive medications within 14 days before starting the study drugs. If you have hepatitis B, you must be on antiviral therapy before joining the trial.

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

Research has shown that the combination of durvalumab and tremelimumab has been tested in patients with liver cancer. These studies found that while some immune-related side effects occur, they are usually not severe, and serious side effects are rare.

Another study found that this combination can cause more immune-related side effects than durvalumab alone, but serious ones remain uncommon. This suggests the treatment is generally well-tolerated.

It is important to note that durvalumab is already approved for treating other types of cancer, providing some confidence in its safety. However, using it with tremelimumab is still under study, so any decision to join a trial should consider this ongoing research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Durvalumab and Tremelimumab for liver cancer because these drugs work by harnessing the power of the immune system. Most current treatments for liver cancer, like surgery, chemotherapy, and radiofrequency ablation, focus on directly targeting and destroying cancer cells. In contrast, Durvalumab and Tremelimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells more effectively. This approach has the potential to provide longer-lasting control of the disease by empowering the body's natural defenses.

What evidence suggests that Durvalumab and Tremelimumab could be effective for liver cancer?

Research shows that using Durvalumab and Tremelimumab together holds promise for treating advanced liver cancer. In earlier studies, this combination helped some patients live five years or more. Participants in this trial will receive a single priming dose of Tremelimumab plus Durvalumab, followed by Durvalumab monotherapy. This combination has effectively controlled the disease and improved outcomes for patients whose liver cancer cannot be surgically removed. The treatment has also demonstrated the ability to keep the cancer under control over time. Overall, evidence suggests this could be a good option for those with advanced liver cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Lorenza Rimassa

Principal Investigator

Humanitas Cancer Centre, IRCCS Humanitas Research Hospital

Stephen Chan, MD

Principal Investigator

Department of Clinical Oncology, Chinese University of Hong Kong

Are You a Good Fit for This Trial?

This trial is for adults with advanced unresectable hepatocellular carcinoma (HCC) who haven't had systemic therapy before. They should have a life expectancy of at least 12 weeks, good organ function, and measurable liver cancer lesions. It's open to those with certain stages of liver disease but excludes anyone with other active cancers, immune conditions, or severe heart issues.

Inclusion Criteria

I have a tumor that can be measured and has not been treated with radiation.

My liver cancer diagnosis was confirmed through a tissue examination.

Minimum life expectancy of 12 weeks

Exclusion Criteria

I have had cancer before, but it fits the exceptions.

I have tested positive for HIV or active tuberculosis.

I have lasting side effects from cancer treatment that are moderate or worse.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive a single priming dose of Tremelimumab plus Durvalumab at Day 1, followed by Durvalumab monotherapy starting at Week 4 and continuing until clinical progression or other criteria are met

Up to 33 months

Safety Follow-up

Participants are monitored for safety and adverse events after treatment

90 days after last dose

Survival Follow-up

Participants are monitored for overall survival and disease progression

Up to 33 months

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Tremelimumab

Trial Overview The study tests the safety and effectiveness of combining two drugs—Durvalumab and Tremelimumab—as a first-line treatment for HCC. These medications are given in a specific regimen called STRIDE to see if they can help control the cancer better than current treatments.

How Is the Trial Designed?

Group I: Durvalumab plus Tremelimumab Experimental Treatment 2 Interventions

Participants will receive a single priming dose of Tremelimumab plus Durvalumab at Day 1 (Week 0), followed by Durvalumab monotherapy starting at Week 4 and continuing until clinical progression, confirmed RECIST 1.1-defined radiological progression, unacceptable toxicity, withdrawal of consent, or any intervention discontinuation criteria.

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 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]

Topical treatment with imiquimod in patients with high-risk melanoma led to a significant increase in local CD4+ and CD8+ T cells in the skin, as well as CD4+ T cells in the sentinel lymph nodes, suggesting an enhanced immune response.

The study indicates that while imiquimod boosts T-cell numbers locally and regionally, it does not increase CD8+ T cells that specifically target melanoma in the peripheral blood, highlighting the need for further research into its immunotherapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation by imiquimod in patients with high-risk primary melanoma. Narayan, R., Nguyen, H., Bentow, JJ., et al.[2021]

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]

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 combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

In a study using C57BL/6 mice, the application of imiquimod combined with a CTL epitope for transcutaneous immunization (TCI) showed that depleting regulatory T cells (T(reg)) significantly enhanced cytotoxic T lymphocyte (CTL) responses, indicating that T(reg) cells suppress immune activation.

The research also found that the cytokine IL-10 plays a crucial role in limiting CTL responses during TCI, as blocking IL-10 signaling or using IL-10 deficient mice led to stronger immune responses, suggesting that targeting both T(reg) and IL-10 could improve vaccination strategies against tumors and persistent infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T cells and IL-10 independently counterregulate cytotoxic T lymphocyte responses induced by transcutaneous immunization. Stein, P., Weber, M., Prüfer, S., et al.[2021]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

A case report describes a patient with metastatic melanoma whose liver and iliac fossa metastases regressed after using imiquimod cream on the skin above the tumors, suggesting a potential new treatment avenue.

This finding indicates that imiquimod, typically used for superficial melanoma, may warrant further research for its efficacy in treating metastatic melanoma, which currently has limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of internal melanoma metastases following application of topical imiquimod to overlying skin. Miller, AK., Dusing, R., Meggison, A., et al.[2018]

Imiquimod (IMI) treatment for 2 weeks in 10 patients with invasive cutaneous squamous cell carcinoma (SCC) significantly increased the local immune response, particularly boosting CD8 T cells, which are crucial for targeting tumors.

The treatment shifted the immune response towards a Th1 and M1 polarization pattern, which is associated with enhanced anti-tumor and anti-viral defense, while reducing the presence of certain macrophage populations, indicating a more effective immune environment against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern. Smith, KJ., Hamza, S., Skelton, H.[2018]

Topical imiquimod (IMQ) significantly suppresses tumor growth in a murine model, with its antitumor effect relying on the production of interferon γ (IFN-γ) by CD8+ T cells, as shown by the abolished effect in Rag1-deficient and IFN-γ-deficient mice.

The combination of topical IMQ and anti-PD-1 antibody therapy shows a significantly enhanced antitumor effect compared to either treatment alone, suggesting it could be an effective strategy for treating skin lesions in various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect. Oya, K., Nakamura, Y., Zhenjie, Z., et al.[2021]

The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among patients with unresectable hepatocellular carcinoma, indicating its potential as an effective treatment option.

All treatment regimens were generally well-tolerated, but T300 + D had the most favorable safety profile, with a significant association between early CD8+ lymphocyte expansion and treatment response, suggesting a promising mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Kelley, RK., Sangro, B., Harris, W., et al.[2022]

In the phase 3 MYSTIC study involving 488 treatment-naïve patients with metastatic non-small-cell lung cancer, durvalumab alone or in combination with tremelimumab showed significant improvements in patient-reported outcomes (PROs) compared to chemotherapy, particularly in reducing fatigue and appetite loss.

Patients receiving durvalumab-containing treatments experienced a longer time to deterioration in quality of life and physical functioning, indicating that these treatments may help maintain better overall well-being without negatively impacting quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Garon, EB., Cho, BC., Reinmuth, N., et al.[2022]

Citations

1. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2024/imfinzi-plus-imjudo-demonstrated-unprecedented-overall-survival-alc-with-one-in-five-patients-surviving-five-years-himalaya-phase-iii-trial.html

Imfinzi plus Imjudo demonstrated unprecedented overall ... AstraZeneca's Imfinzi (durvalumab) plus Imjudo (tremelimumab) demonstrated a sustained, clinically meaningful overall survival (OS) benefit at five years.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05027425

Study Details | NCT05027425 | Durvalumab (MEDI4736) ... Immunotherapy can safely downstage patients and achieve durable systemic disease control to improve clinical outcomes in HCC patients undergoing liver ...

3. imfinzihcp.com imfinzihcp.com/hcc/unresectable/efficacy.html

Efficacy Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10841291/

FDA Approval Summary: Tremelimumab in combination ... The KM estimate for median PFS was 3.8 months (95% CI: 3.7, 5.3) in the tremelimumab plus durvalumab arm, and 4.1 months (95% CI: 3.7, 5.5) in the sorafenib arm ...

5. imfinzi.com imfinzi.com/hepatocellular-carcinoma/about-imfinzi/clinical-trial-results.html

5-YEAR FOLLOW-UP RESULTS - IN uHCC Find the 5-year clinical trial results for IMFINZI® (durvalumab) + IMJUDO® (tremelimumab-actl), a treatment for adults diagnosed with unresectable ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06911255

Safety and Efficacy of Tremelimumab+Durvalumab ... The purpose of this clinical trial is to evaluate the safety and efficacy of tremelimumab + durvalumab administered concurrently with transarterial ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06526104

NCT06526104 | Study of Tremelimumab and Durvalumab ... It can be used to predict the prognosis of patients with liver cirrhosis and hepatocellular carcinoma, and has been shown to be more accurate than the Child- ...

8. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12128435/

Differential safety profiles of durvalumab monotherapy and ... Higher incidences of imAEs were observed with D+T compared with D monotherapy across tumor types; however, fatal imAEs were infrequent and similar in both ...

10. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/520275

Study of Tremelimumab and Durvalumab ... - Carebox Connect The invesitgators hypothesize that T300+D will be safe and tolerated in CP-B patients with HCC. HCC mostly affects disadvantaged populations ...