Atezolizumab + Bevacizumab + Memantine for Liver Cancer

((HCC) Trial)

Overseen by Arthur Winer, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Inova Health Care Services

Must not be taking: Memantine

Disqualifiers: Childs-Pugh B/C cirrhosis, Pregnancy, HIV, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this research is to see the effect of triplet therapy with atezolizumab, bevacizumab, and memantine in treatment of your hepatocellular carcinoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are already on memantine, you cannot participate. It's best to discuss your current medications with the study team to see if they might affect your eligibility.

What data supports the effectiveness of the drug combination Atezolizumab, Bevacizumab, and Memantine for liver cancer?

The combination of atezolizumab and bevacizumab is considered the standard first-line treatment for liver cancer that cannot be surgically removed, showing better results than previous treatments. This combination has been shown to enhance the body's immune response against cancer and improve outcomes in patients with liver cancer. ^{1 2 3 4 5}

Is the combination of Atezolizumab and Bevacizumab safe for liver cancer patients?

While Atezolizumab and Bevacizumab are generally considered safe, there have been reports of serious side effects like encephalitis (brain inflammation) and transverse myelitis (spinal cord inflammation) in some liver cancer patients. ^{1 6 7 8 9}

What makes the drug combination of Atezolizumab, Bevacizumab, and Memantine unique for liver cancer?

The combination of Atezolizumab and Bevacizumab is already a standard first-line treatment for advanced liver cancer, known for improving survival compared to older treatments like Sorafenib. Adding Memantine, typically used for Alzheimer's disease, is novel and may offer additional benefits, although its specific role in liver cancer treatment is not yet well understood. ^{1 3 10 11 12}

Research Team

Arthur Winer, MD

Principal Investigator

Principal Investigator

Eligibility Criteria

This trial is for individuals with hepatocellular carcinoma, a type of liver cancer. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have no conflicting conditions.

Inclusion Criteria

My cancer cannot be removed with surgery and is advanced.

Patients must demonstrate the ability to understand and the willingness to sign a written informed consent document

I am eligible for this study regardless of my gender, race, ethnicity, or sexual orientation.

Exclusion Criteria

My liver cancer is of a specific rare type.

I have pain from my cancer that isn't managed well.

I haven't had major surgery or a serious injury in the last 28 days.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive triplet therapy with atezolizumab, bevacizumab, and memantine in 21-day cycles

6 months

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Treatment Details

Interventions

• Atezolizumab, Bevacizumab (Checkpoint Inhibitor, Monoclonal Antibodies)
• Memantine (Other)

Trial Overview The study investigates the combined effect of three drugs: Atezolizumab (an immunotherapy), Bevacizumab (a drug that inhibits blood vessel growth in tumors), and Memantine Hydrochloride (commonly used for Alzheimer's disease) on liver cancer.

Participant Groups

Group I: Addition of Memantine to Atezolizumab and Bevacizumab (the current systemic standard of care) Experimental Treatment 3 Interventions

The study intervention consists of the use of the triplet therapy (atezolizumab, bevacizumab, and memantine) given in 21-day cycles over six months.

Who Is Running the Clinical Trial?

Inova Health Care Services

Lead Sponsor

Trials

80

Recruited

22,700+

Dr. J. Stephen Jones

Inova Health Care Services

Chief Executive Officer since 2018

MD from University of Pennsylvania, MPH and MBA from George Washington University

Dr. Maureen Sintich

Inova Health Care Services

Chief Medical Officer since 2019

MD from George Washington University

Findings from Research

In a study of 191 patients with unresectable hepatocellular carcinoma (HCC), the combination therapy of atezolizumab and bevacizumab showed similar overall survival and progression-free survival rates in older patients (≥65 years) compared to younger patients (<65 years), indicating its efficacy across age groups.

The safety profile of the combination therapy was comparable between older and younger patients, with similar rates of treatment-related adverse events, including severe adverse events, suggesting that older patients can tolerate this treatment as well as younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Vithayathil, M., D'Alessio, A., Fulgenzi, CAM., et al.[2023]

In a study of 1447 patients treated with tyrosine-kinase inhibitors for hepatocellular carcinoma, only 29% were eligible for the combination therapy of atezolizumab-bevacizumab based on the IMbrave-150 trial criteria, indicating limited real-world applicability.

Eligible patients showed a median overall survival of 14.9 months, which was longer than non-eligible patients, suggesting that those who meet the criteria have better baseline health and cancer characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. Stefanini, B., Bucci, L., Santi, V., et al.[2022]

In a phase 1b study involving 223 patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab resulted in a significantly longer median progression-free survival of 5.6 months compared to 3.4 months for atezolizumab alone, indicating enhanced efficacy of the combination treatment.

The most common serious treatment-related adverse events included hypertension and proteinuria, with a treatment-related death rate of 3% in the combination group, suggesting that while the combination therapy is effective, it does carry some safety risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lee, MS., Ryoo, BY., Hsu, CH., et al.[2020]

In a study of 766 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, those who met the IMbrave150 trial inclusion criteria had significantly longer overall survival (16.3 months) compared to those who did not (14.3 months).

Among patients who did not meet the IMbrave150 criteria, those with a better liver function (ALBI grade 1) experienced a notable survival benefit, with a median overall survival of 16.7 months compared to 5.9 months for those with ALBI grade 2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? Rimini, M., Persano, M., Tada, T., et al.[2023]

In a phase 3 trial involving 501 patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab significantly improved overall survival (67.2% at 12 months) and progression-free survival (6.8 months) compared to sorafenib.

The treatment with atezolizumab-bevacizumab showed a lower risk of death (hazard ratio 0.58) and similar rates of severe adverse events compared to sorafenib, indicating a favorable safety profile despite some instances of grade 3 or 4 hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. Finn, RS., Qin, S., Ikeda, M., et al.[2021]

A 70-year-old woman with advanced hepatocellular carcinoma developed severe encephalitis after just one cycle of the combination therapy with atezolizumab and bevacizumab, highlighting a rare but serious adverse effect of this treatment.

Rapid immunosuppressive treatment with high-dose steroids and plasmapheresis led to clinical improvement in the patient's encephalitis, although she ultimately succumbed to progressive liver cancer, indicating the need for careful monitoring of neurological symptoms in patients receiving immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review. Özdirik, B., Jost-Brinkmann, F., Savic, LJ., et al.[2023]

In a study of 286 patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab, treatment-related hypertension was linked to better progression-free survival, with a median of 12.6 months compared to 6.5 months for those without hypertension.

Conversely, treatment-related fatigue was associated with shorter overall survival, indicating that while hypertension may signal a positive response to treatment, fatigue could indicate poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Tada, T., Kumada, T., Hiraoka, A., et al.[2023]

The IMbrave150 study supports the use of atezolizumab and bevacizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC), indicating its efficacy in this patient population.

However, this combination therapy can lead to serious side effects, as demonstrated by a case of transverse myelitis occurring during treatment, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma. Kim, KH., Baek, YH., Kang, YW., et al.[2023]

This case report describes a 42-year-old woman with hepatocellular carcinoma who developed encephalitis after receiving atezolizumab and bevacizumab therapy, highlighting a potential serious immune-related adverse effect of these treatments.

Despite treatment with steroid pulse therapy leading to some improvement in symptoms, the patient continued to experience lasting effects, such as right-sided paralysis and aphasia, indicating that while the therapy can be effective, it may also carry significant risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab-induced Encephalitis in a Patient with Hepatocellular Carcinoma: A Case Report and Literature Review. Satake, T., Maruki, Y., Kubo, Y., et al.[2022]

The combination therapy of atezolizumab and bevacizumab shows potential as a treatment option for patients with both hepatocellular carcinoma and gastric adenocarcinoma.

This finding suggests a possible new approach for managing these concurrent cancers, although further studies are needed to confirm its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatocellular carcinoma with gastric adenocarcinoma treated with atezolizumab and bevacizumab. Suga, T., Kimura, Y., Furuya, K., et al.[2023]

Atezolizumab combined with bevacizumab demonstrated good efficacy in treating advanced hepatocellular carcinoma (HCC), with a pooled overall response rate of 26% and a median overall survival of 14.7 months based on a review of 23 studies involving 3168 patients.

The treatment was well-tolerated, with 83% of patients experiencing any grade adverse events, and 30% experiencing grade 3 or higher adverse events, indicating that while side effects are common, the combination therapy remains a viable first-line option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. Gao, X., Zhao, R., Ma, H., et al.[2023]

Atezolizumab plus bevacizumab improves overall survival and quality-adjusted life-years (QALYs) compared to sorafenib in patients with unresectable or metastatic hepatocellular carcinoma, with an increase of 0.623 life-years and 0.484 QALYs in a hypothetical sample of 424 patients.

Despite the clinical benefits, the treatment is not cost-effective, with an incremental cost-effectiveness ratio (ICER) of $322,500 per QALY, indicating that significant price reductions of 37% to 47% for atezolizumab and bevacizumab would be necessary to make it a more viable option compared to sorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib for Patients With Unresectable or Metastatic Hepatocellular Carcinoma. Zhang, X., Wang, J., Shi, J., et al.[2021]

References

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

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors. [2022]

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

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. [2020]

4. France pubmed.ncbi.nlm.nih.gov

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? [2023]

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

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. [2021]

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

Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review. [2023]

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

Adverse events as potential predictive factors of therapeutic activity in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. [2023]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

Atezolizumab-induced Encephalitis in a Patient with Hepatocellular Carcinoma: A Case Report and Literature Review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Hepatocellular carcinoma with gastric adenocarcinoma treated with atezolizumab and bevacizumab. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. [2023]

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

Cost-effectiveness of Atezolizumab Plus Bevacizumab vs Sorafenib for Patients With Unresectable or Metastatic Hepatocellular Carcinoma. [2021]