Immunomodulators + Anticancer Agents for Hepatobiliary Cancer

Recruiting at 39 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

260 Participants Needed

Trial Summary

What is the purpose of this trial?

GEMINI-Hepatobiliary study will assess the efficacy, safety and tolerability of novel immunomodulators alone and in combination with other anticancer drugs in participants with specified advanced solid tumors.

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.

What data supports the effectiveness of the drug combination of lenvatinib and anti-PD-1 antibodies for hepatocellular carcinoma?

Research shows that lenvatinib combined with anti-PD-1 antibodies has demonstrated strong anti-tumor effects in patients with advanced or unresectable hepatocellular carcinoma (HCC), particularly in those with significant liver tumor involvement. This combination is more effective than using either drug alone, although some patients may not respond due to specific immune cell interactions. ^{1 2 3 4 5}

What safety data exists for the combination of immunomodulators and anticancer agents in treating hepatobiliary cancer?

Studies have shown that lenvatinib, when used alone or in combination with other drugs like anti-PD-1 or bevacizumab, has been evaluated for safety in treating liver cancer. These treatments have been generally considered safe, but as with any medication, they can have side effects, and their impact on liver function has been specifically studied. ^{1 6 7 8 9}

How is the drug combination of Bevacizumab, Lenvatinib, and MEDI5752 unique for treating hepatobiliary cancer?

This drug combination is unique because it combines immunotherapy with targeted therapy, using Bevacizumab and Lenvatinib to normalize blood vessels and enhance the immune response, while MEDI5752, a bispecific antibody, targets two immune checkpoints to boost the body's ability to fight cancer. ^{1 5 10 11 12}

Eligibility Criteria

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

My organs and bone marrow are working well.

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

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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 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 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 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]

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 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]

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]

References

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

Population Sensitive to Lenvatinib Plus Anti-PD-1 for Unresectable Hepatocellular Carcinoma Infected with Hepatitis B Virus. [2023]

2. United States 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Real-world efficiency of lenvatinib plus PD-1 blockades in advanced hepatocellular carcinoma: an exploration for expanded indications. [2022]

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

MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway. [2023]

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

Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. [2022]

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

Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. [2023]

7. United States 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. [2023]

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

Clinical impact of lenvatinib in patients with unresectable hepatocellular carcinoma who received sorafenib. [2022]

9. Switzerland 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. [2023]

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

T-Cell Subsets as Potential Biomarkers for Hepatobiliary Cancers and Selection of Immunotherapy Regimens as a Treatment Strategy. [2022]

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

Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies. [2023]

12. Switzerland 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. [2023]