Immunotherapy for Liver Cancer

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Academic and Community Cancer Research United

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Pregnancy, Major surgery, Autoimmune disorders, 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: 2

Duration: Up to 18 months

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period of at least 4 weeks since the last dose of atezolizumab and bevacizumab. It does not specify other medications, so you should discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination of Ipilimumab, Yervoy, Nivolumab, and Opdivo for liver cancer?

Research shows that combining nivolumab with ipilimumab can improve outcomes for patients with advanced liver cancer, as seen in the CheckMate 040 trial. Additionally, nivolumab alone has been associated with increased survival and manageable safety in liver cancer patients. ^{1 2 3 4 5}

Is immunotherapy for liver cancer generally safe for humans?

Immunotherapy drugs like Ipilimumab and Nivolumab have been used for various cancers and are generally considered safe, but they can cause side effects. Common side effects include skin issues, inflammation of the colon, liver, and hormone glands, and in rare cases, severe immune-related reactions that can affect different organs. ^{6 7 8 9 10}

How is the drug combination of ipilimumab and nivolumab unique for treating liver cancer?

The combination of ipilimumab and nivolumab is unique for treating liver cancer because it targets immune checkpoints to boost the body's immune response against cancer cells, especially after other immune therapies have failed. This approach is different from traditional treatments as it uses the body's own immune system to fight the cancer. ^{11 12 13 14 15}

What is the purpose of this trial?

This trial tests if two drugs, nivolumab and ipilimumab, can shrink tumors in patients with advanced liver cancer who haven't responded to other treatments. These drugs help the immune system attack and kill cancer cells.

Research Team

Mehmet Akce

Principal Investigator

Academic and Community Cancer Research United

Eligibility Criteria

Adults with advanced liver cancer that has spread or can't be surgically removed, who have previously been treated with Atezolizumab + Bevacizumab and need a new treatment. They must meet specific health criteria like certain blood cell counts and liver function tests, not be pregnant or breastfeeding, use contraception if of childbearing potential, and cannot have had major surgery or other treatments recently.

Inclusion Criteria

Willing to provide mandatory tissue specimens and blood specimens for correlative research purposes

Absolute neutrophil count (ANC) >= 1000/mm ^ 3 (obtained =< 28 days prior to registration)

Total bilirubin =< 3 x upper limit of normal (ULN) (obtained =< 28 days prior to registration)

Exclusion Criteria

I have had cancer spread to the lining of my brain and spinal cord.

Nursing persons

I have not had a heart attack in the last 6 months and don't need ongoing therapy for severe heart rhythm problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab and ipilimumab intravenously. Treatment repeats every 21 days for 4 cycles, followed by nivolumab every 28 days for up to 24 cycles.

Up to 18 months

1 visit every 21 days for 4 cycles, then 1 visit every 28 days for up to 24 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 2 years

1 visit at 30 days post-treatment, then every 3 months

Treatment Details

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the combination of two immunotherapy drugs called Nivolumab and Ipilimumab to see if they can shrink tumors in patients with advanced liver cancer. These drugs may help the immune system fight the cancer more effectively.

Participant Groups

Group I: Treatment (nivolumab, ipilimumab) Experimental Treatment 2 Interventions

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Academic and Community Cancer Research United

Lead Sponsor

Trials

54

Recruited

4,900+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 11 patients with advanced hepatocellular carcinoma (HCC), nivolumab therapy demonstrated a high disease control rate of 81.8% and an objective response rate of 63.6%, indicating its efficacy as a treatment option.

No adverse effects related to nivolumab were reported, suggesting a favorable safety profile, especially for patients who did not respond to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma. Feng, D., Hui, X., Shi-Chun, L., et al.[2022]

In a phase 1/2 study involving 148 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, the combination of nivolumab and ipilimumab showed a promising objective response rate of 32% in one treatment arm, indicating potential efficacy for this patient population.

The treatment regimen was generally manageable in terms of safety, although 94% of patients in one arm experienced treatment-related adverse events, highlighting the need for careful monitoring; notably, this combination therapy received accelerated approval in the US based on these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. Yau, T., Kang, YK., Kim, TY., et al.[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 71 patients with advanced hepatocellular carcinoma, the combination of nivolumab and cabozantinib showed promising antitumor activity, with an objective response rate of 17% for the doublet therapy and 29% for the triplet therapy including ipilimumab.

Both treatment combinations had manageable safety profiles, with 50% of patients in the doublet arm and 74% in the triplet arm experiencing grade 3-4 treatment-related adverse events, but no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. Yau, T., Zagonel, V., Santoro, A., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

In a study of 1480 cancer patients treated with immune checkpoint inhibitors (ICIs), over 50% experienced hepatic adverse events (AEs), with 14.9% classified as severe (grade 3-4).

The presence of hepatic AEs was linked to poorer overall survival rates, with median survival dropping from 9.0 months for patients without AEs to just 3.3 months for those with severe hepatic AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. Chan, SL., Yip, TC., Wong, VW., et al.[2021]

Patients with hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors experienced significant increases in liver enzymes (AST and ALT) compared to those with melanoma and non-small cell lung cancer (NSCLC), indicating a potential for liver-related side effects.

Despite the elevated liver enzymes, the study found that these patients did not have higher rates of treatment discontinuation or death due to drug toxicity, suggesting that immune checkpoint inhibitors are safe for use in HCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. Brown, ZJ., Heinrich, B., Steinberg, SM., et al.[2018]

A review of 2217 adverse drug reaction reports related to immune checkpoint inhibitors (ICIs) from 2011 to 2018 revealed that these drugs, particularly nivolumab, are associated with a higher frequency of serious immune-related adverse events, including gastrointestinal and respiratory disorders.

Emerging safety signals, such as ischaemic heart disease and cardiac failure, were identified, indicating the need for further investigation into the long-term safety profile of ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. Cutroneo, PM., Isgrò, V., Ientile, V., et al.[2021]

Ipilimumab, a monoclonal antibody that enhances T-cell immune responses, is FDA-approved for treating advanced melanoma but is associated with significant immune-related side effects.

Common adverse effects include dermatitis, colitis, and hepatitis, with rare cases like bilateral orbital inflammatory syndrome reported, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case report of orbital inflammatory syndrome secondary to ipilimumab. Henderson, AD., Thomas, DA.[2018]

Immune checkpoint inhibitors like nivolumab have revolutionized cancer treatment but can lead to serious autoimmune-like side effects known as immune-related adverse events (irAEs).

This study highlights a specific case of severe liver injury linked to nivolumab in a glioblastoma patient, emphasizing the need for better understanding and management of these potential toxicities to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Simonelli, M., Di Tommaso, L., Baretti, M., et al.[2018]

In a study of 10 patients with advanced hepatocellular carcinoma (HCC) who had previously failed ICI-based treatments, the combination of ipilimumab and nivolumab showed an overall response rate of 30% and a disease control rate of 40%.

The median progression-free survival was 2.9 months and median overall survival was 7.4 months, indicating that this treatment combination is both effective and tolerable for patients with advanced HCC after prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study. Roessler, D., Öcal, O., Philipp, AB., et al.[2023]

Ipilimumab (Yervoy®) is an approved monoclonal antibody for treating malignant melanoma by blocking the CTLA-4 protein, which enhances T-cell responses against tumor cells, showing its efficacy in cancer immunotherapy.

Currently, ipilimumab is also being tested in phase III trials for prostate cancer and phase II trials for non-small cell lung cancer, indicating its potential for broader applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: first global approval. Cameron, F., Whiteside, G., Perry, C.[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]

Ipilimumab, a monoclonal antibody used to enhance anti-tumor T-cell responses, can cause significant side effects, including ipilimumab-induced hypophysitis (IH), which affects hormone levels and requires hormone replacement therapy in most cases.

In a review of 10 patients with IH, early detection and management guidelines were developed, highlighting the importance of monitoring hormone levels and recognizing imaging abnormalities, which often resolve without high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. Lam, T., Chan, MM., Sweeting, AN., et al.[2022]

In a study of 25 patients with advanced hepatocellular carcinoma (HCC) who had previously progressed on immune checkpoint inhibitors (ICIs), the combination of ipilimumab with nivolumab or pembrolizumab showed a 16% objective response rate, indicating some effectiveness in overcoming prior treatment resistance.

The treatment resulted in a median overall survival of 10.9 months, with 42.4% of patients surviving at least one year, while 52% experienced treatment-related adverse events, suggesting that the combination therapy has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. Wong, JSL., Kwok, GGW., Tang, V., et al.[2022]

References

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

Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma. [2022]

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

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. [2022]

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

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. [2023]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

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

Pattern and impact of hepatic adverse events encountered during immune checkpoint inhibitors - A territory-wide cohort study. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. [2021]

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

A case report of orbital inflammatory syndrome secondary to ipilimumab. [2018]

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

Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. [2018]

11. Germany pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study. [2023]

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

Ipilimumab: first global approval. [2021]

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

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

14. Australia pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series. [2022]

15. England pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. [2022]