Durvalumab + Tremelimumab for Liver Cancer

(SIERRA Trial)

Recruiting at40 trial locations

Overseen by Lorenza Rimassa

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: AstraZeneca

Must be taking: Antivirals

Must not be taking: Immunosuppressants, Torsades de Pointes

Disqualifiers: Heart failure, Autoimmune disorders, HIV, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This study will assess the safety and efficacy of Single Tremelimumab Regular Interval Durvalumab (STRIDE) as first-line therapy in participants with advanced unresectable HCC.

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.

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

The combination of Durvalumab and Tremelimumab was approved by the FDA for treating liver cancer based on a study showing it improved overall survival compared to another drug, sorafenib. Patients lived a median of 16.4 months with the combination, compared to 13.8 months with sorafenib. ^{1 2 3 4 5}

Is the combination of Durvalumab and Tremelimumab safe for humans?

The combination of Durvalumab and Tremelimumab has been studied for safety in various cancers, showing that serious side effects (like severe diarrhea and reduced appetite) are more common compared to using Durvalumab alone. Common side effects include rash, fatigue, diarrhea, itching, muscle pain, and abdominal pain. ^{1 2 3 6 7}

How is the drug combination of Durvalumab and Tremelimumab unique for treating liver cancer?

The combination of Durvalumab and Tremelimumab is unique because it uses two immune checkpoint inhibitors that work together to enhance the body's immune response against cancer cells, which is different from traditional chemotherapy that directly targets and kills cancer cells. ^{8 9 10 11 12}

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

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Durvalumab (Checkpoint Inhibitor)
• Tremelimumab (Checkpoint Inhibitor)

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.

Participant Groups

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 Japan for the following indications:

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

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 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]

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]

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]

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]

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]

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]

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]

References

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

Tremelimumab: First Approval. [2023]

2. 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]

3. United States 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. [2022]

4. United States 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). [2022]

5. United States 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. [2022]

6. Switzerland 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. [2023]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

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

Regression of internal melanoma metastases following application of topical imiquimod to overlying skin. [2018]

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

Immunomodulation by imiquimod in patients with high-risk primary melanoma. [2021]

10. England 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. [2018]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect. [2021]

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

Regulatory T cells and IL-10 independently counterregulate cytotoxic T lymphocyte responses induced by transcutaneous immunization. [2021]