IRX-2 + Cyclophosphamide + Nivolumab for Liver Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for liver cancer that has returned or spread and does not respond to usual treatments. It combines IRX-2, a biological therapy that may help the immune system fight cancer, with cyclophosphamide, a chemotherapy drug that can stop cancer cells from growing, and nivolumab, an immunotherapy that helps the body attack cancer. The goal is to find the best dose and understand the side effects of using these treatments together. This trial is for people with liver cancer that has come back or spread and who have already tried other treatments without success.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research shows that the combination of IRX-2, cyclophosphamide, and nivolumab is under evaluation for safety and effectiveness in treating liver cancer. Previous studies suggest that this combination might outperform IRX-2 alone for liver cancer that has spread or recurred.

Nivolumab, an immunotherapy drug, has demonstrated success in other liver cancer studies by aiding the immune system in attacking cancer cells. Cyclophosphamide, a chemotherapy drug, stops cancer cells from growing or spreading.

As this trial is in its first phase, it focuses on determining the safest doses of these drugs. This phase often marks the first time a treatment is tested in humans, aiming to identify any side effects and assess tolerance. While some safety aspects remain unknown, the trial will gather important information. Participants in this study could help discover new treatment options for liver cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of IRX-2, cyclophosphamide, and nivolumab for liver cancer because it offers a multi-pronged approach that could enhance treatment effectiveness. Unlike standard treatments that often rely solely on chemotherapy or targeted therapy, this regimen incorporates immunotherapy with nivolumab, which boosts the body's immune response to fight cancer. IRX-2 is a novel cytokine-based therapy that may further stimulate the immune system, potentially improving outcomes beyond current options like sorafenib and lenvatinib. Additionally, using cyclophosphamide could help modulate the immune environment to be more favorable for these therapies to work synergistically, offering a new hope for liver cancer patients.

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

Research suggests that combining IRX-2, cyclophosphamide, and nivolumab, as studied in this trial, may be more effective for liver cancer than using IRX-2 alone. Nivolumab, included in this trial, is an immune therapy that has controlled the disease in about 20% of liver cancer patients. Cyclophosphamide, another treatment in this trial, stops cancer cells from growing or spreading. The combination aims to strengthen the immune system and directly attack cancer cells. Early studies indicate that this combination shows promise for treating liver cancer that has recurred or metastasized. ^{1 2 3 6 7}

Who Is on the Research Team?

Daneng Li

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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 the IRX-2 regimen before.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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 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 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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03655002

IRX-2, Cyclophosphamide, and Nivolumab in Treating ... Giving IRX-2, cyclophosphamide, and nivolumab may work better than the IRX?2 regimen alone in treating patients with hepatocellular carcinoma. Detailed ...

2. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT03655002?keyword=%22Stage%20IVB%20Hepatocellular%20Carcinoma%22

IRX-2, Cyclophosphamide, and Nivolumab in Treating ... Giving IRX-2, cyclophosphamide, and nivolumab may work better than the IRX?2 regimen alone in treating patients with hepatocellular carcinoma. Criteria: Source: ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9400240/

A comprehensive review about the utilization of immune ... In recent years, ICIs have been revealed to have a successful therapeutic result on HCC patients, with a disease control rate of around 20% [85, ...

4. opdivohcp.com opdivohcp.com/efficacy/hcc

Efficacy Data for Hepatocellular Carcinoma (HCC) In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab (n=268). Grade 3 and 4 adverse reactions occurred in 42% ...

5. onclive.com onclive.com/view/immunotherapy-combo-shows-signs-of-efficacy-in-2-hcc-settings

Immunotherapy Combo Shows Signs of Efficacy in 2 HCC ... Using dual checkpoint inhibitors in patients with hepatocellular carcinoma (HCC) is demonstrating activity with a manageable safety profile in both second-line ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-00863

IRX-2, Cyclophosphamide, and Nivolumab in Treating ... Giving IRX-2 and cyclophosphamide with nivolumab may work better than nivolumab alone in treating patients with recurrent or metastatic solid tumors.

7. europepmc.org europepmc.org/article/pmc/pmc8012774

Hepatocellular Carcinoma Immune Landscape and the ... A Study of Nivolumab in Combination With Ipilimumab in Participants With Advanced Hepatocellular Carcinoma (CheckMate 9DW) ... Liver Cancer, Drug: Nivolumab