Nivolumab +/− Relatlimab for Liver Cancer

Not currently recruiting at 1 trial location

Overseen By Joann Santmyer, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

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 You can continue your current medications while participating

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and tolerability of two treatments, Nivolumab and Relatlimab, for individuals with liver cancer (HCC). Participants will receive either Nivolumab alone or a combination of Nivolumab and Relatlimab to determine which is more effective in preparing the body for surgery or aiding recovery afterward. The trial seeks individuals with liver cancer that can be surgically removed and who have not received previous systemic treatments for their cancer. Those with liver cancer confined to the liver and meeting these conditions may be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

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

Research has shown that using Nivolumab alone for liver cancer carries some risks. In rare cases, serious side effects such as lung inflammation and muscle weakness have occurred, affecting less than 1% of patients. Overall, Nivolumab's side effects are generally manageable.

When combined with Relatlimab, studies indicate that this combination is generally safe. The side effects resemble those known for each drug individually. While some side effects may occur, they are typically expected from similar treatments.

In summary, both Nivolumab alone and the Nivolumab-Relatlimab combination have side effects considered tolerable. However, like any treatment, potential risks exist, and participants should discuss these with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Nivolumab and Relatlimab for liver cancer because these treatments target the immune system in unique ways. Nivolumab is a checkpoint inhibitor that unleashes the immune system by blocking the PD-1 pathway, helping T cells attack cancer cells more effectively. Relatlimab also works as a checkpoint inhibitor but targets the LAG-3 protein, offering an additional pathway to boost the immune response. This dual-action approach is different from traditional treatments like chemotherapy and targeted therapies, which don't directly engage the immune system in the same way. By combining these two drugs, researchers hope to achieve a more robust and sustained anti-cancer response, potentially improving outcomes for patients with liver cancer.

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

Studies have shown that Nivolumab, one of the treatments in this trial, effectively treats liver cancer, specifically hepatocellular carcinoma (HCC). It has been proven to shrink tumors or make them disappear in more patients compared to traditional treatments like lenvatinib or sorafenib. In one study, patients using Nivolumab lived an average of 23.7 months, longer than those on other treatments. Another arm of this trial will test the combination of Nivolumab and Relatlimab. Research indicates that this combination can produce stronger responses than Nivolumab alone, especially in other cancers like melanoma, suggesting it might work well for liver cancer too. ^{2 3 4 6 7}

Who Is on the Research Team?

Mark Yarchoan, MD

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

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

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.

My cancer has not spread outside the liver, to lymph nodes, or to both sides of the portal vein.

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).

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Relatlimab

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union 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 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+

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

Published Research Related to This Trial

Nivolumab, a PD-1 inhibitor, has demonstrated significant safety and efficacy in treating various advanced solid tumors, including melanoma and lung cancer, based on multiple high-level studies.

Future research should aim to identify predictive biomarkers for treatment response and explore the potential of combining nivolumab with other therapies, as well as determining the best treatment strategies and duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

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 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]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

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. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., 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]

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]

In a phase III trial, the combination of the LAG3 immune checkpoint inhibitor relatlimab with the PD-1 inhibitor nivolumab significantly improved progression-free survival for melanoma patients, more than doubling the time without disease progression.

The combination therapy was associated with relatively manageable side effects, suggesting it could be a safe and effective addition to current melanoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

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]

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]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/hcc

Efficacy Data for Hepatocellular Carcinoma (HCC) Liver-related serious adverse reactions occurred in 17% of patients receiving OPDIVO with YERVOY, including Grade 3-4 events in 16% of patients. The most ...

2. opdivo.com opdivo.com/advanced-hcc/clinical-trial-results/unresectable-immunotherapy-combination

Clinical trial results for previously untreated advanced liver ... More people given OPDIVO + YERVOY had their tumors shrink or completely disappear compared to targeted therapies lenvatinib or sorafenib ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7338665/

Real-World Outcomes of Nivolumab in Patients With ... In conclusion, our study demonstrates that nivolumab monotherapy is clinically efficacious in treating unresectable HCC in an endemic area of HBV infection.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9644453/

Low-dose nivolumab in advanced hepatocellular carcinoma Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC.

5. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma

FDA approves nivolumab with ipilimumab for unresectable ... Median OS was 23.7 months (95% CI: 18.8, 29.4) in the nivolumab + ipilimumab arm and 20.6 months (95% CI: 17.5, 22.5) in the lenvatinib or ...

6. opdivohcp.com opdivohcp.com/safety/hcc/opdivo-yervoy

Safety Profile in Hepatocellular Carcinoma (HCC) - Opdivo Fatal adverse reactions occurring in 3 (0.9%) patients who received OPDIVO as a single agent; these included pneumonitis (n=2) and myasthenia gravis. In ...

7. karger.com karger.com/pjg/article/doi/10.1159/000543288/918492/Five-year-sustained-response-to-nivolumab-in

Five-Year Sustained Response to Nivolumab in ... Second-line nivolumab, although yielding a rapid clinical and biochemical response, was permanently ceased after 12 weeks due to a grade 3 ...