Immunomodulators + Anticancer Agents for Hepatobiliary Cancer

Recruiting at 47 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Disqualifiers: Autoimmune disorders, Uncontrolled illness, Active infection, others

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

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: 24 weeks

294 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for advanced hepatobiliary cancer, which affects the liver, bile ducts, or gallbladder. Researchers are testing novel immunomodulators—drugs that help the immune system fight cancer—both alone and in combination with other anticancer drugs like bevacizumab (Avastin) and lenvatinib (Lenvima). The goal is to assess the effectiveness and safety of these treatments for patients. Individuals with a confirmed diagnosis of advanced hepatobiliary cancer who have not received certain prior treatments might be suitable for this study. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that each treatment in the trial has some safety information available.

For **Volrustomig**, studies indicate it targets two different molecules to help the immune system fight cancer and is generally well-tolerated. However, like many cancer treatments, it can cause side effects, such as tiredness and low blood cell counts.

**Rilvegostomig** has been tested with chemotherapy and has a manageable safety profile. While side effects can occur, medical support usually addresses them. Common side effects might include nausea and tiredness, similar to other treatments in its category.

**Bevacizumab** is an approved treatment for several cancers with extensive safety data. It is generally well-tolerated but can cause high blood pressure and bleeding problems. These risks are well-known, and doctors monitor patients closely during treatment.

**Lenvatinib** is also a well-researched drug used for other cancers. Safety data show it can cause side effects like high blood pressure and tiredness. These are typical for its type of drug, and doctors usually manage them successfully.

Overall, while each treatment can have side effects, they have been studied extensively. Patients should talk to their healthcare provider about any concerns to understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for hepatobiliary cancer because they explore unique combinations and mechanisms that could offer new hope for patients. Unlike the standard of care that often involves chemotherapy drugs like Gemcitabine and Cisplatin, these investigational treatments incorporate novel immunomodulators like Volrustomig and Rilvegostomig. Volrustomig, in particular, is being tested as both a monotherapy and in combination with other agents such as Bevacizumab and Lenvatinib, potentially enhancing its anti-cancer effects. Rilvegostomig is also being studied in conjunction with established drugs like Bevacizumab and chemotherapy agents to see if it can boost treatment outcomes. These innovative approaches could offer more effective options by targeting cancer cells in new ways and potentially improving patient survival rates.

What evidence suggests that this trial's treatments could be effective for hepatobiliary cancer?

Research has shown that volrustomig, a special type of antibody, effectively treats some cancers. In earlier studies, this treatment helped 58% of patients with advanced kidney cancer, suggesting potential effectiveness for other cancers like liver and bile duct cancer. In this trial, some participants will receive volrustomig alone, while others will receive it with bevacizumab, a drug that cuts off the tumor's blood supply, potentially enhancing effectiveness. Another group will receive rilvegostomig, which showed good results with chemotherapy drugs like gemcitabine and cisplatin for advanced bile duct cancer. This combination has been safe and more effective than standard treatments. These findings suggest these treatments could be promising for liver and bile duct cancer, but ongoing trials will provide more information. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced hepatobiliary cancer, which includes liver and biliary tract cancers. Participants must have a measurable tumor that hasn't been treated with radiation, be expected to live at least 12 weeks, and can provide a tumor sample. It's not for those who've had organ transplants, hepatic encephalopathy in the last year, previous study participation or certain infections and autoimmune diseases.

Inclusion Criteria

Provision of a signed and dated written ICF

Life expectancy of at least 12 weeks at the time of screening

My organs and bone marrow are working well.

Exclusion Criteria

I do not have an active infection, brain metastases, or spinal cord compression.

Previous treatment in the present study

I have both hepatitis B and D.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Volrustomig or Rilvegostomig as monotherapy or in combination with anticancer agents

24 weeks

Regular visits throughout treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for long-term safety and survival outcomes

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Lenvatinib
• MEDI5752

Trial Overview The GEMINI-Hepatobiliary study is testing new immune-modifying drugs (AZD2936 & MEDI5752) alone or combined with other cancer treatments (Cisplatin, Gemcitabine, Bevacizumab & Lenvatinib). The goal is to see how effective and safe these combinations are for treating specific advanced solid tumors of the liver and bile ducts.

How Is the Trial Designed?

Group I: Cohort 2B Experimental Treatment 3 Interventions

Volrustomig combination with Gemcitabine and Cisplatin

Group II: Cohort 2A Experimental Treatment 3 Interventions

Rilvegostomig combination with Gemcitabine and Cisplatin

Group III: Cohort 1E Experimental Treatment 2 Interventions

Rilvegostomig combination with bevacizumab

Group IV: Cohort 1D Experimental Treatment 3 Interventions

Volrustomig combination with rilvegostomig and bevacizumab

Group V: Cohort 1C Experimental Treatment 2 Interventions

Volrustomig combination with lenvatinib

Group VI: Cohort 1B Experimental Treatment 2 Interventions

Volrustomig combination with bevacizumab

Group VII: Cohort 1A Experimental Treatment 1 Intervention

Volrustomig monotherapy

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

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

An optimal dose of lenvatinib was found to effectively normalize tumor blood vessels and enhance immune cell infiltration in both immunodeficient and immunocompetent mouse models, suggesting a promising approach to improve immunotherapy outcomes in hepatocellular carcinoma (HCC).

The study identified specific mechanisms by which lenvatinib promotes vascular normalization, including the formation of the NRP-1-PDGFRβ complex and activation of the Crkl-C3G-Rap1 signaling pathway, which together enhance the efficacy of immune checkpoint blockade therapies like anti-PD-1 antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib improves anti-PD-1 therapeutic efficacy by promoting vascular normalization via the NRP-1-PDGFRβ complex in hepatocellular carcinoma. Yang, J., Guo, Z., Song, M., et al.[2023]

Advanced hepatocellular and biliary cancers have poor outcomes with standard therapies, but hepatocellular carcinoma shows potential for immunotherapy due to its immune-infiltrated microenvironment.

Understanding the behavior of T cells and immune modulators in the tumor microenvironment is essential for developing effective combination therapies and identifying response markers for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy. Kumar-Sinha, C., Sahai, V.[2022]

In a study of 40 patients with unresectable hepatocellular carcinoma (HCC) who received lenvatinib after sorafenib, the median overall survival was 9.8 months, indicating that lenvatinib is an effective treatment option in this setting.

Most side effects from lenvatinib were mild (grades 1-2), suggesting that it is generally well-tolerated by patients, reinforcing its safety as a second-line or later treatment for HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of lenvatinib in patients with unresectable hepatocellular carcinoma who received sorafenib. Chen, YY., Wang, CC., Liu, YW., et al.[2022]

In a study of 84 patients with advanced hepatocellular carcinoma (HCC), those treated with lenvatinib plus PD-1 blockades had a median progression-free survival (PFS) of 6.6 months and overall survival (OS) of 11.4 months, indicating the treatment's potential effectiveness.

Patients with tumor occupation ≥50% (TO ≥50%) experienced significantly worse outcomes compared to those with lower tumor occupation, suggesting that TO ≥50% is a critical prognostic factor for PFS and OS in HCC patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world efficiency of lenvatinib plus PD-1 blockades in advanced hepatocellular carcinoma: an exploration for expanded indications. Sun, X., Zhang, Q., Mei, J., et al.[2022]

In a study of 92 patients with unresectable hepatocellular carcinoma (HCC), lenvatinib showed similar efficacy to the combination of atezolizumab and bevacizumab (A+B) in terms of objective response rate, progression-free survival, and overall survival, indicating that both treatments are viable first-line options.

The safety profiles of lenvatinib and A+B were comparable, with similar rates of adverse events and minimal impact on liver function, suggesting that both therapies are safe for patients with HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Su, CW., Teng, W., Lin, PT., et al.[2023]

In a study involving 59 patients with advanced hepatocellular carcinoma, the combination of cadonilimab and lenvatinib showed an objective response rate of approximately 35.5% to 35.7%, with a median duration of response around 13.6 months, indicating promising efficacy as a first-line treatment.

While the treatment was effective, it also had a significant safety profile, with 66.1% of patients experiencing grade ≥ 3 treatment-related adverse events, including common issues like decreased platelet count and hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of cadonilimab combined with lenvatinib for first-line treatment of advanced hepatocellular carcinoma (COMPASSION-08): a phase Ib/II single-arm clinical trial. Qiao, Q., Han, C., Ye, S., et al.[2023]

The combination of lenvatinib and anti-PD1 antibodies enhances treatment efficacy in hepatocellular carcinoma (HCC) by activating the TNF-NFKB pathway across various immune cell types, as shown through single-cell sequencing of samples from six HCC patients.

Mucosal-associated invariant T (MAIT) cells play a role in promoting immunosuppression by secreting TNF, which activates regulatory T cells, highlighting a potential mechanism of resistance in over half of HCC patients who do not respond to this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway. Zhou, C., Sun, BY., Zhou, PY., et al.[2023]

In a phase Ib study involving 104 patients with unresectable hepatocellular carcinoma (uHCC), the combination of lenvatinib and pembrolizumab demonstrated significant antitumor activity, with an objective response rate of 46% according to modified RECIST criteria.

The treatment was well-tolerated, with manageable toxicities and no new safety signals identified, indicating that this combination could be a viable option for patients with uHCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. Finn, RS., Ikeda, M., Zhu, AX., et al.[2022]

In a study of 70 patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV), combining lenvatinib with at least 3 cycles of anti-PD-1 therapy significantly improved overall survival (21.4 months) and progression-free survival (8.0 months) compared to lenvatinib alone (14 months and 6.3 months, respectively).

Patients with portal vein trunk invasion or extrahepatic spread, particularly those with Child-Pugh class B liver function, experienced the greatest benefit from the combination therapy, showing a 38% increase in 12-month survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Sensitive to Lenvatinib Plus Anti-PD-1 for Unresectable Hepatocellular Carcinoma Infected with Hepatitis B Virus. Chang, X., Yu, S., Pang, J., et al.[2023]

In a study of 210 patients with advanced or unresectable hepatocellular carcinoma (HCC), the combination of lenvatinib and anti-PD-1 antibodies showed an objective response rate of 28.1% and a disease control rate of 75.2%, indicating significant anti-tumor efficacy in a real-world setting.

Patients with better liver function (Child-Pugh class A) experienced longer median overall survival (18.8 months) compared to those with poorer liver function (Child-Pugh class B, 5.9 months), highlighting the importance of liver function in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of lenvatinib plus anti-programmed death-1 antibodies in patients with hepatocellular carcinoma: A real-world cohort study. Xu, MH., Huang, C., Li, ML., et al.[2023]

In a study of 648 matched patients with hepatocellular carcinoma, both atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) led to a significant worsening of liver function, as measured by the ALBI score, over 12 weeks, but there was no significant difference in deterioration rates between the two treatments.

Subgroup analyses indicated that LEN-treated patients with advanced BCLC stage or those receiving the full dose experienced a greater decline in liver function, suggesting that caution is needed when using LEN in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach. Hatanaka, T., Kakizaki, S., Hiraoka, A., et al.[2023]

In a study analyzing T cell subsets in patients with hepatopancreaticobiliary (HPB) cancers, it was found that while various T cell types were present, their anti-tumor functions were often inhibited by co-inhibitory checkpoint receptors, particularly in pancreatic ductal adenocarcinoma (PDA).

Hepatocellular carcinoma (HCC) patients showed a higher presence of tissue resident memory T cells that could potentially respond better to immune checkpoint therapies, suggesting that HCC may benefit more from these combined therapies compared to PDA and cholangiocarcinoma (CCA), which may require different treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies. Wan, S., Zhao, E., Weissinger, D., et al.[2023]

Citations

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Retrospective Multicentre Real-Life Study Evaluating the ... The ImBrave 150 trial successfully demonstrated that overall survival (OS) and progression-free survival (PFS) was improved among patients ...

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Avastin® (bevacizumab) Efficacy, Safety, Dosing & ... Avastin is extensively studied: Avastin FDA approvals based on 12 pivotal trials across 7 tumor types.

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avastin - accessdata.fda.gov The safety data in Warnings and Precautions and described below reflect exposure to Avastin in 4463 patients including those with mCRC (AVF2107g, E3200), non- ...

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Risks and benefits with bevacizumab Bevacizumab is a safe and effective drug utilized in several cancers. The quest for reliable predictive markers remains of utmost importance.

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Bevacizumab (intravenous route) - Side effects & uses Bevacizumab injection is also used together with atezolizumab to treat a type of liver cancer ... Safety and efficacy have not been established.