Trial Summary
What is the purpose of this trial?This study will investigate if modulating the tumor microenvironment with biologic agents like XL-092 will have synergistic effect when combined with checkpoint based immunotherapeutic treatment of patients with hepatocellular carcinoma (HCC).
Is the drug combination of Durvalumab, Tremelimumab, and Zanzalintinib promising for liver cancer?Yes, the combination of Durvalumab and Tremelimumab has shown promise in treating liver cancer. These drugs have been approved for use in patients with advanced liver cancer, and studies suggest they can help improve survival rates. The addition of Zanzalintinib, although not specifically mentioned in the studies, could potentially enhance the treatment's effectiveness.23467
What safety data is available for the combination of Zanzalintinib, Durvalumab, and Tremelimumab in liver cancer treatment?The combination of Durvalumab and Tremelimumab has been studied for safety in various trials. In the HIMALAYA study, adverse reactions in ≥20% of patients included rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. A systematic review and meta-analysis found that the combination had a higher incidence of Grade 3 or higher adverse events (32.6%) compared to Durvalumab alone (23.8%). Common adverse events included reduced appetite and diarrhea. The combination is considered to have a tolerable safety profile in patients with solid tumors, including liver cancer.15678
What data supports the idea that Zanzalintinib + Immunotherapy for Liver Cancer is an effective drug?The available research shows that the combination of Zanzalintinib (also known as tremelimumab) and durvalumab has been approved for treating liver cancer that cannot be removed by surgery. This approval suggests that the drug combination is effective. Additionally, studies have shown that this combination provides clinical benefits and has a tolerable safety profile for patients with solid tumors, which includes liver cancer. This means that patients can experience positive outcomes without severe side effects. While other treatments like tivozanib combined with durvalumab are being explored, the specific approval and positive results for Zanzalintinib and durvalumab highlight its effectiveness for liver cancer.12367
Do I have to stop taking my current medications for the trial?The trial protocol does not specify if you must stop all current medications. However, you cannot take certain medications like oral anticoagulants, some complementary medicines, and certain anticancer therapies close to the start of the trial. It's best to discuss your specific medications with the trial team.
Eligibility Criteria
This trial is for individuals with unresectable hepatocellular carcinoma (HCC), which is a type of liver cancer that cannot be removed by surgery. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have no conflicting conditions.Inclusion Criteria
Urine protein-to-creatinine ratio (UPCR) must be ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine. Tumor tissue fresh biopsies are REQUIRED for ALL study participants at screening/baseline unless an archival tumor tissue block is available and fulfills the criteria.
My liver cancer cannot be removed with surgery.
I am 18 or older and can care for myself with minimal assistance.
I am using effective birth control methods if I'm sexually active.
I have not received any systemic therapy for my condition that cannot be surgically removed.
I am not pregnant and can become pregnant.
Exclusion Criteria
I have a history of lung conditions or currently have lung inflammation.
My liver function is severely impaired.
I have recently had radiation therapy or treatment with radioactive substances.
I am taking blood thinners.
I do not have ongoing infections, non-healing wounds, digestive issues, liver problems, or need dialysis.
I cannot swallow pills.
I have an autoimmune disease treated with long-term immunosuppressants.
I have an immune system disorder or have recently been on steroids.
I have had liver-related brain issues or significant fluid in my abdomen recently.
Treatment Details
The study tests the combination of Zanzalintinib (XL-092) with two immunotherapy drugs, Durvalumab and Tremelimumab, to see if they work better together in treating liver cancer by modifying the tumor environment.
3Treatment groups
Experimental Treatment
Active Control
Group I: Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV)Experimental Treatment3 Interventions
Safety Lead-in: XL-092: Dose escalation or de-escalation - Level 1 = 100 mg; Level 0 = 60 mg; Level -1 = 40 mg. The first dose level (dose level 0) will follow the rolling 6 design. Starting with cycle 1 then cycle 3 and subsequent cycles, participants will receive XL-092 60 mg orally (PO) once daily on days 1 through 28 of every 28-day cycle. Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 2; Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 2 day 1
Group II: Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (First Cyle Durvalumab + Tremelimumab)Active Control3 Interventions
Phase 2: XL092 dose as determined by results of safety lead-in phase orally (PO). Once daily on days 1 - 28 of every 28-day cycle. Dosing will start with cycle 2.
Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 1.
Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 1 day 1
Group III: Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (First Cyle Zanzalintinib)Active Control3 Interventions
Phase 2: XL092 dose as determined by results of safety lead-in phase orally (PO). Once daily on days 1 - 28 of every 28-day cycle. Dosing will start with cycle 1 then cycle 3 and subsequent cycles.
Durvalumab: Flat dose of 1500 mg intravenously (IV) Infusion on day 1 of every 28-day cycle. Dosing will start with cycle 2; Tremelimumab (IV): One priming dose of 300 mg IV infusion. The dose will be given with cycle 2 day 1
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:
UPMC Hillman Cancer CenterPittsburgh, PA
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Who is running the clinical trial?
Anwaar SaeedLead Sponsor
ExelixisIndustry Sponsor
References
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.
Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. [2021]The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in.
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).
Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial. [2022]Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.
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
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.
A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.
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.