Nivolumab +/− Relatlimab for Liver Cancer

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Mark Yarchoan, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Antivirals

Must not be taking: Chemotherapy, Immunotherapy, Steroids

Disqualifiers: HIV, Autoimmune, Cardiovascular, others

Stay on Your Current Meds

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the safety and tolerability of neoadjuvant/adjuvant Nivolumab or Nivolumab plus Relatlimab in patients with HCC.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy or have a history of autoimmune disease requiring treatment, you may not be eligible to participate.

What data supports the effectiveness of the drug Nivolumab +/− Relatlimab for liver cancer?

Nivolumab, one of the drugs in the combination, has shown to improve survival and provide durable responses in patients with advanced liver cancer. Additionally, the combination of nivolumab and relatlimab has been effective in treating melanoma, suggesting potential benefits for other cancers. ^{1 2 3 4 5}

Is the combination of Nivolumab and Relatlimab safe for humans?

Nivolumab, used in various cancer treatments, has been associated with liver injury and immune-related side effects, such as hepatitis B reactivation and bile duct damage. These effects have been observed in patients with liver cancer and other conditions, indicating potential safety concerns that should be monitored. ^{6 7 8 9 10}

How is the drug Nivolumab + Relatlimab unique for liver cancer treatment?

Nivolumab + Relatlimab is unique because it combines two immunotherapy drugs that target different immune checkpoints, PD-1 and LAG-3, to enhance the body's immune response against cancer. This combination is novel as it includes Relatlimab, a first-in-class drug, which is not commonly used in standard liver cancer treatments. ^{1 2 11 12 13}

Research Team

Mark Yarchoan, MD

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Eligibility Criteria

This trial is for adults with Hepatocellular Carcinoma (HCC) that can potentially be removed by surgery. Participants should have good performance status, no spread of cancer outside the liver, and meet specific heart function criteria. They must not have had prior systemic chemotherapy or certain immunotherapies for HCC, nor should they have other significant health issues like uncontrolled diseases or a history of HIV.

Inclusion Criteria

I am 18 years old or older.

Must use acceptable form of birth control while on study.

My heart's pumping ability is normal, confirmed by a test within the last 6 months.

Exclusion Criteria

I have been treated with specific immune therapies before.

You have a known or suspected allergic reaction to the study treatment.

I am not taking high doses of steroids (> 10 mg/day of prednisone or equivalent).

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant Nivolumab or Nivolumab plus Relatlimab

8 weeks

Surgery

Participants undergo surgical resection of hepatocellular carcinoma

Adjuvant Treatment

Participants receive adjuvant Nivolumab or Nivolumab plus Relatlimab

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Nivolumab (Checkpoint Inhibitor)
• Relatlimab (Checkpoint Inhibitor)

Trial Overview The study tests the safety and effectiveness of Nivolumab alone or combined with Relatlimab before and after surgery in patients with HCC. It aims to see how well these drugs work when given around the time of tumor removal.

Participant Groups

Group I: Arm B - Nivolumab and Relatlimab Experimental Treatment 2 Interventions

Participants receive Nivolumab and Relatlimab.

Group II: Arm A - Nivolumab Experimental Treatment 1 Intervention

Participants receive Nivolumab only.

Nivolumab is already approved in Canada, Switzerland for the following indications:

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Dr. William G. Nelson

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Director since 1992

MD, PhD

Dr. Elizabeth Jaffee

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Chief Medical Officer since 2023

MD

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Nivolumab plus relatlimab is a combination immunotherapy that targets immune checkpoints, specifically PD-1 and LAG-3, and has been approved for treating unresectable or metastatic melanoma in adults and adolescents weighing at least 40 kg.

This combination therapy represents a significant advancement in cancer treatment, as it utilizes two different mechanisms to enhance the immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab: First Approval. Paik, J.[2022]

In a study of 129 patients with advanced melanoma treated with nivolumab and relatlimab, those without diabetes had significantly better progression-free survival (PFS) and overall survival (OS) compared to patients with type 2 diabetes, indicating that diabetes negatively impacts treatment efficacy.

Interestingly, patients who developed immune checkpoint inhibitor-induced diabetes (ICI-DM) during treatment had the best outcomes, suggesting that this condition may enhance the effectiveness of the therapy, possibly due to changes in LAG3 expression in tumor tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. Mallardo, D., Woodford, R., Menzies, AM., et al.[2023]

Nivolumab, a PD-1 inhibitor, showed durable responses and increased overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC), with a median OS of 28.1 months for patients with PD-L1 expression ≥1% compared to 16.6 months for those with <1%.

The study found that higher expression of PD-1 and PD-L1, along with specific inflammatory gene signatures, were associated with improved survival and response to treatment, suggesting that the immune response plays a significant role in the effectiveness of nivolumab in HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. Sangro, B., Melero, I., Wadhawan, S., et al.[2022]

In a study of 194 advanced hepatocellular carcinoma (HCC) patients treated with nivolumab, a baseline neutrophil-lymphocyte ratio (NLR) of 3 or higher was linked to significantly poorer overall survival, indicating that NLR can be a useful prognostic marker.

An increase in NLR at 4 weeks of treatment was predictive of hyperprogression and associated with a higher risk of death, suggesting that monitoring NLR changes during treatment could help tailor immunotherapy strategies for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma. Choi, WM., Kim, JY., Choi, J., et al.[2021]

In a study of 46 patients with advanced cancer, those with HIV or hepatitis B/C infections showed responses to anti-PD-1/PD-L1 immunotherapy without increased toxicity, suggesting that these populations can safely receive this treatment.

Among solid organ transplant patients, there was a risk of graft rejection (2 out of 6 patients), highlighting the need for careful consideration of anti-PD-1/PD-L1 therapy in this group despite some achieving partial responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection. Tio, M., Rai, R., Ezeoke, OM., et al.[2023]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, shows effectiveness in treating hepatocellular carcinoma (HCC), particularly in a subset of patients receiving it in the neoadjuvant setting, with marked treatment responses observed in some cases.

Long-term nivolumab therapy may lead to specific liver injuries, such as bile duct damage and ductular reactions, indicating the need for further studies to understand these effects and identify patients who may benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy. Simoes, CC., Thung, SN., Fiel, MI., et al.[2023]

In a retrospective study of 26 patients with metastatic renal cell carcinoma treated with nivolumab, all patients experienced some form of adverse event, with fatigue, fever, and anemia being the most common, affecting 27% of patients.

Despite the occurrence of adverse events, including grade 3 reactions in 23% of patients, nivolumab demonstrated favorable safety outcomes in a real-life clinical setting, consistent with findings from other studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting. Amores Bermúdez, J., Osman García, I., Unda Urzáiz, M., et al.[2021]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

In a retrospective analysis of 34 advanced HCC patients treated with nivolumab, the treatment was found to be safe, with only 5.9% experiencing grade 3 toxicities, indicating a manageable safety profile.

The overall survival for patients was relatively short, with a median of 7.5 weeks, and those with Child-Pugh B stage disease had significantly poorer outcomes, suggesting that nivolumab's efficacy may be limited in patients with advanced liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. Finkelmeier, F., Czauderna, C., Perkhofer, L., et al.[2020]

References

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

Nivolumab Plus Relatlimab: First Approval. [2022]

2. England pubmed.ncbi.nlm.nih.gov

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. [2022]

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

Kinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma. [2021]

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

LAG3-PD-1 Combo Impresses in Melanoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

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

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. [2023]

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

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy. [2023]

10. Spain pubmed.ncbi.nlm.nih.gov

Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting. [2021]

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

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

12. Germany pubmed.ncbi.nlm.nih.gov

Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. [2020]

13. England pubmed.ncbi.nlm.nih.gov

An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. [2018]