IRX-2 + Cyclophosphamide + Nivolumab for Liver Cancer

Recruiting at 2 trial locations

Overseen By Daneng Li

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, others

Disqualifiers: Autoimmune disorders, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

8 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial studies the side effects and best dose of IRX-2 when given together with cyclophosphamide and nivolumab in treating patients with liver cancer that has come back or spread to other parts of the body and does not response to treatment. Biological therapies, such as IRX-2, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving IRX-2, cyclophosphamide, and nivolumab may work better than the IRX?2 regimen alone in treating patients with hepatocellular carcinoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medications within 14 days before starting nivolumab, except for certain low-dose steroids and local steroid treatments. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the drug Nivolumab for liver cancer?

Nivolumab, when combined with another drug called ipilimumab, has shown improved outcomes in patients with advanced liver cancer, as seen in the CheckMate 040 trial. This suggests that Nivolumab may be beneficial for liver cancer treatment, especially when used in combination with other therapies. ^{1 2 3 4 5}

Is the combination of IRX-2, Cyclophosphamide, and Nivolumab generally safe for humans?

Nivolumab, a part of this treatment, can cause immune-related side effects affecting various organs like the skin, endocrine system, digestive system, and kidneys. These side effects can be serious, but they are not common, with severe cases occurring in about 6% of patients. Cyclophosphamide is a chemotherapy drug that can also have side effects, but specific safety data for the combination with IRX-2 is not available. ^{6 7 8 9 10}

What makes the drug combination of IRX-2, Cyclophosphamide, and Nivolumab unique for liver cancer?

This treatment is unique because it combines IRX-2, an immune system booster, with Cyclophosphamide, a chemotherapy drug, and Nivolumab, an immune checkpoint inhibitor, to potentially enhance the body's immune response against liver cancer. This combination aims to leverage different mechanisms to target cancer cells, which is different from standard treatments that typically use single agents. ^{1 2 11 12 13}

Research Team

Daneng Li

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults with advanced liver cancer that has returned or spread and isn't responding to treatment. Participants must have certain blood counts, weigh over 30 Kg, have a specific liver function score (Child-Pugh class A), and be able to give informed consent. They should not have had more than three prior treatments for their condition and must not be pregnant or breastfeeding.

Inclusion Criteria

My liver cancer cannot be treated with surgery or radiation aimed at a cure.

I have had up to three treatments for my cancer that has returned or spread.

I am fully active or can carry out light work.

Exclusion Criteria

I have not had major surgery in the last 28 days.

I have been treated with PD-1/PD-L1 inhibitors before.

I have been treated with the IRX-2 regimen before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive nivolumab IV on day 1, cyclophosphamide IV on day 1, and IRX-2 SC for 10 days between days 4 and 15. Cycles repeat every 28 days for up to 18 months.

18 months

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 12 weeks

Quarterly visits

Treatment Details

Interventions

• Cyclophosphamide
• IRX-2
• Nivolumab

Trial Overview The study is testing the combination of IRX-2 (a biological therapy), cyclophosphamide (chemotherapy), and nivolumab (an immunotherapy) to see if this trio is more effective than previous treatments for hepatocellular carcinoma. The trial will determine the best dose of IRX-2 when used with the other drugs.

Participant Groups

Group I: Treatment (nivolumab, cyclophosphamide, IRX-2) Experimental Treatment 3 Interventions

Patients receive nivolumab IV over 30 minutes on day 1, cyclophosphamide IV on day 1, and IRX-2 SC for 10 days between days 4 and 15. Cycles repeat every 28 days for up to 18 months in the absence of disease progression or unacceptable toxicity. Patients receive booster IRX-2 SC at 3, 6, 9, 12, and 15 months.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

In a phase 3 trial involving 1150 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab with two cycles of chemotherapy significantly improved overall survival compared to chemotherapy alone, with a median survival of 15.6 months versus 10.9 months.

The treatment regimen showed a favorable safety profile, with serious treatment-related adverse events occurring in 30% of the experimental group compared to 18% in the control group, indicating that the benefits of the combination therapy outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Paz-Ares, L., Ciuleanu, TE., Cobo, M., et al.[2021]

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]

In the phase III CheckMate 9LA trial with 30.7 months of follow-up, the combination of nivolumab and ipilimumab with chemotherapy significantly improved overall survival (OS) in patients with advanced non-small-cell lung cancer, with a median OS of 15.8 months compared to 11.0 months for chemotherapy alone.

The combination treatment also showed a manageable safety profile, with no new safety signals and most severe treatment-related adverse events occurring during the first two cycles, indicating it is a viable first-line option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. Reck, M., Ciuleanu, TE., Cobo, M., et al.[2021]

In a study of 69 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival (OS) and progression-free survival compared to those without irAEs, suggesting that irAEs may be a positive indicator of treatment response.

The study identified three key factors influencing OS: the presence of irAEs, C-reactive protein levels, and performance status, indicating that monitoring these factors could help predict patient outcomes in mRCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Nukaya, T., Takahara, K., Yoshizawa, A., et al.[2023]

In a meta-analysis of 46 studies involving 12,808 cancer patients treated with anti-PD-1/PD-L1 agents, the overall incidence of immune-related adverse events (irAEs) was found to be 26.82%, with severe irAEs occurring in 6.10% of patients.

The types of irAEs varied by organ system and were influenced by the specific drug and cancer type, but the occurrence of these adverse events was not related to the dosage of the PD-1 inhibitors, indicating a need for careful monitoring regardless of treatment levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Wang, PF., Chen, Y., Song, SY., et al.[2022]

In a study of 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

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 phase II clinical trial involving 55 patients with melanoma, a one-year regimen of low-dose nivolumab resulted in an 85.7% relapse-free survival rate, suggesting it could be an effective treatment option.

The combination of a shorter low-dose nivolumab with ipilimumab was found to be less effective and more prone to adverse events, indicating that longer treatment with nivolumab alone may be preferable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial. Schwarze, JK., Garaud, S., Jansen, YJL., et al.[2022]

References

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

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. [2018]

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

Nivolumab: a review in advanced squamous non-small cell lung cancer. [2022]

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

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. [2021]

4. 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]

5. England pubmed.ncbi.nlm.nih.gov

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. [2021]

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

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. [2023]

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

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. [2022]

8. Australia pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced toxicities and the gastroenterologist. [2017]

9. England pubmed.ncbi.nlm.nih.gov

Nivolumab-associated acute glomerulonephritis: a case report and literature review. [2022]

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

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

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

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial. [2022]