Durvalumab + Tremelimumab for Liver Cancer
Recruiting in Palo Alto (17 mi)
Overseen byDaneng Li
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Breakthrough Therapy
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.
12345Is 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.
12367How 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.
89101112Eligibility 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.
+28 more
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
+23 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (durvalumab, tremelimumab)Experimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Tremelimumab: First Approval. [2023]Tremelimumab (tremelimumab-actl; IMJUDO®), a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibody, is being developed by AstraZeneca, under license from Pfizer, for the treatment of a range of malignant tumours. Tremelimumab was approved in the USA in October 2022 in combination with durvalumab for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). In addition, tremelimumab in combination with durvalumab and platinum-based chemotherapy was approved in the USA in November 2022 for the treatment of adult patients with metastatic non-small cell lung cancer (mNSCLC) with no sensitizing epidermal growth factor receptor mutation or anaplastic lymphoma kinase genomic tumour aberrations. In December 2022, tremelimumab in combination with durvalumab received a Positive Opinion from the EU Committee for Medicinal Products for Human Use for the first line treatment of adults with advanced or unresectable HCC. Tremelimumab in combination with durvalumab is under regulatory review for these indications in Japan and in other countries worldwide. This article summarizes the milestones in the development of tremelimumab leading to this first approval.
FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. [2023]On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma (uHC). The approval was based on the results from the HIMALAYA study, in which patients with uHC who were naïve to previous systemic treatment were randomized to receive one of three study arms: tremelimumab in combination with durvalumab (n=393), durvalumab (n=389), or sorafenib (n=389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared to sorafenib met statistical significance with a stratified hazard ratio (HR) of 0.78 (95% confidence interval [CI], 0.66, 0.92; P=0.0035). The median OS was 16.4 months (95% CI, 14.2 to 19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3 to 16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg intravenous (IV) as a single dose in combination with durvalumab 1500 mg at Cycle 1/Day 1, followed by durvalumab 1500 mg IV every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg IV as a single dose in combination with durvalumab 20 mg/kg IV, followed by durvalumab 20 mg/kg IV every 4 weeks.
Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors.
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]The phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).
Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. [2022]This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).
Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]Background: Recently, the combination of durvalumab and tremelimumab, two immune checkpoint inhibitors, for the treatment of different types of cancers has been considered; however, its overall effects, including its safety, are still unclear and need to be further investigated. Objectives: The aim of the present systematic review and meta-analysis was to investigate the safety and tolerability of this combination of drugs. Methods: A systematic review of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, was conducted by employing online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. The selection of eligible publications was made following a staged screening and selection process. The software RevMan 5.4 was used to run the quantitative analysis and forest plots, while the Cochrane tool was employed for risk of bias assessment. Results: From the retrieved 157 results, 9 randomized controlled trials involving 3060 patients were included. By comparing the combination of durvalumab and tremelimumab vs. durvalumab monotherapy, it was observed that: adverse events (AEs) ≥ Grade 3 incidence was 32.6% (536/1646) vs. 23.8% (336/1414) (Z = 2.80; p = 0.005; risk ratio (RR) = 1.44), reduced appetite incidence was 10.8% (154/1427) vs. 8.3% (108/1305) (Z = 2.26; p = 0.02; RR = 1.31), diarrhea was reported in 15.6% (229/1473) vs. 8.1% (110/1352) (Z = 5.90; p
Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.
Regression of internal melanoma metastases following application of topical imiquimod to overlying skin. [2018]The prognosis for metastatic melanoma is grim, and treatment options are limited. Imiquimod is a topically applied immune modulator that has been used to treat superficial cutaneous melanoma, but has not been reported to treat metastatic melanoma. We report a patient whose liver and iliac fossa melanoma metastases regressed after topical application of imiquimod cream to overlying skin. This supports further investigation of the potential use of imiquimod for metastatic melanoma.
Immunomodulation by imiquimod in patients with high-risk primary melanoma. [2021]Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.
Topical imidazoquinoline therapy of cutaneous squamous cell carcinoma polarizes lymphoid and monocyte/macrophage populations to a Th1 and M1 cytokine pattern. [2018]Imidazoquinolines are topical immune response modifiers. Imiquimod (IMI), the first imidazoquinoline, is approved for the treatment of genital human papillomavirus disease and has shown success as a therapeutic agent for cutaneous premalignant and malignant tumours. To define the pattern of polarization of the local immune response to invasive cutaneous squamous cell carcinoma (SCC) we pretreated 10 SCCs that were > 3 cm in diameter for 2 weeks with IMI. The tumours were treated on Monday, Wednesday and Friday and excised the next Monday. A battery of immunohistochemical markers was used to define the mononuclear cell populations in the diagnostic, and the excisional biopsy specimens. The total inflammatory infiltrate was increased after IMI therapy: the greatest increase was in the CD8 T cells with a marked relative decrease in the CD68 monocytic/macrophages; the majority of the CD8 T cells showed expression of cytotoxic granules, T cell-restricted intracellular antigen (TIA) and granzyme B. The relative numbers of monocytes/macrophages were decreased after therapy with IMI with a decrease in CD68+, CD23+, and CD14+ cells and an increase in MAC-397+, and factor XIIIa+ cells. The epidermal dendritic cells showed a > 75% decrease in CD1a+ cells. The immunohistochemical marker profile after IMI therapy is consistent with that induced by a Th1 and M1 cytokine polarization pattern. This cytokine pattern is known to be more effective in defence against tumours as well as viral infections.
Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect. [2021]The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.
Regulatory T cells and IL-10 independently counterregulate cytotoxic T lymphocyte responses induced by transcutaneous immunization. [2021]The imidazoquinoline derivate imiquimod induces inflammatory responses and protection against transplanted tumors when applied to the skin in combination with a cognate peptide epitope (transcutaneous immunization, TCI). Here we investigated the role of regulatory T cells (T(reg)) and the suppressive cytokine IL-10 in restricting TCI-induced cytotoxic T lymphocyte (CTL) responses.