Durvalumab + Tremelimumab for Liver Cancer

Overseen By Daneng Li

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Anti-PD-1/PD-L1, Anti-CTLA4

Disqualifiers: Metastatic disease, Autoimmune disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

Duration: 12 months

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial investigates the side effects of durvalumab and tremelimumab after radioembolization (radiation particles against liver tumors) and to see how well they work in treating patients with liver cancer that cannot be removed by surgery (unresectable) and has spread to nearby tissues and lymph nodes (locally advanced). Durvalumab and tremelimumab are antibodies (proteins produced by the defense system of the body \[immune system\]) that have been made in the laboratory and may improve the ability of the immune system to detect and fight 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 be on any concurrent chemotherapy, investigational products, or immunosuppressive medications within 14 days before starting the study drugs. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination 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 this 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) occurred in about 32.6% of patients, compared to 23.8% with Durvalumab alone. Common side effects in liver cancer patients included 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

Daneng Li

Principal Investigator

City of Hope Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with advanced liver cancer that can't be removed by surgery and hasn't spread beyond the liver. Candidates must have a life expectancy of at least 12 weeks, measurable disease, adequate organ function, no history of certain treatments or conditions that could interfere with the study, and agree to use contraception if applicable.

Inclusion Criteria

Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as outlined in RECIST version 1.1

International normalized ration =< 1.6

My liver function is classified as Child-Pugh A.

Exclusion Criteria

My cancer has spread to other parts of my body.

I haven't taken immunosuppressive drugs in the last 14 days.

Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radioembolization

Patients undergo standard of care radioembolization with Yttrium-90 SIR-spheres intra-arterially over 60-90 minutes

1 day

1 visit (in-person)

Treatment

Patients receive durvalumab and tremelimumab intravenously. Durvalumab cycles repeat every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

Every 12 weeks

Treatment Details

Interventions

• Durvalumab
• Tremelimumab

Trial Overview The trial tests Durvalumab and Tremelimumab after radioembolization in patients with unresectable liver cancer. These lab-made antibodies may boost the immune system's ability to fight cancer following targeted radiation therapy aimed at liver tumors.

Participant Groups

Group I: Treatment (durvalumab, tremelimumab) Experimental Treatment 2 Interventions

Patients undergo standard of care radioembolization with Yttrium-90 SIR-spheres intra-arterially over 60-90 minutes on day -14. Patients then receive durvalumab IV over 1 hour and tremelimumab IV over 1 hour on day 1. Cycles with durvalumab repeat every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity.

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?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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 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]

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]

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]

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]