Siltuximab for Advanced Cancer

Overseen By The Ohio State University Comprehensive Cancer Cener

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Yuanquan Yang

Must be taking: Anti-PD1, Anti-PD-L1

Must not be taking: High-dose corticosteroids

Disqualifiers: Pregnancy, Autoimmune disease, HIV, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 31

Duration: 18-24 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well giving siltuximab during the reintroduction (rechallenge) of immune checkpoint inhibitor (ICI) therapy works in preventing severe immune-related adverse events (irAEs) in patients with cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1 monoclonal antibodies, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The use of ICI therapy may lead to severe irAEs that can affect essentially any organ system in the body. Severe irAEs may lead to the early stopping of life saving treatment. Most patients that stop ICI therapy early will eventually progress and require additional treatment. Sometimes the decision is made to rechallenge with ICI therapy. Many patients who developed severe irAEs during initial ICI therapy are at risk for developing severe irAEs again during the rechallenge. Siltuximab is a monoclonal antibody that binds to receptors for a protein called interleukin-6 (IL-6). This may help lower the body's immune response and reduce inflammation. Giving siltuximab during ICI rechallenge may help prevent severe irAEs in patients with advanced cancer.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be off high-dose systemic corticosteroids for at least 2 weeks before starting the study treatment, and chronic steroid use up to 10 mg daily prednisone is allowed.

What data supports the effectiveness of the drug Siltuximab for advanced cancer?

Siltuximab has shown effectiveness in treating multicentric Castleman disease, with 34% of patients experiencing a significant response compared to none in the placebo group. Additionally, it has been studied for its potential benefits in prostate cancer and ovarian cancer by targeting the interleukin-6 pathway, which is involved in cancer growth. ^{1 2 3 4 5}

Research Team

Yuanquan Yang

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for patients with advanced cancer who previously had severe immune-related side effects from ICI therapy. It's designed to see if siltuximab can prevent these side effects when the ICI treatment is tried again.

Inclusion Criteria

Serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)

I am able to care for myself and perform daily activities.

Hemoglobin > 7 g/dL and < 17 g/dL

Exclusion Criteria

High risk for bowel perforation per the investigator's judgment, such as history of severe diverticulitis or active ulcers or extensive gastrointestinal (GI) involvement by the tumor

I am not pregnant or breastfeeding.

Known unmanageable allergies, hypersensitivity, intolerance to monoclonal antibodies, to murine, chimeric, human proteins or their excipients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive anti-PD1 or anti-PD-L1 monoclonal antibody therapy and siltuximab intravenously. Treatment repeats every 3 weeks for up to 8 doses or every 4 weeks for up to 6 doses.

18-24 weeks

Every 3 or 4 weeks, depending on treatment cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at day 28, every 12 weeks for up to 2 years, and then every 6 months until 5 years following registration.

5 years

Day 28, every 12 weeks for 2 years, then every 6 months

Treatment Details

Interventions

• Siltuximab

Trial Overview The CIRES trial is testing whether administering siltuximab, a drug that targets inflammation, can help avoid serious immune system reactions in patients undergoing a second round of ICI therapy for advanced cancer.

Participant Groups

Group I: Treatment (PD1 antibody, PD-L1 antibody, Siltuximab) Experimental Treatment 9 Interventions

Patients receive anti-PD1 or anti-PD-L1 monoclonal antibody therapy either every 3 or 6 weeks, or every 2 or 4 weeks per physicians choice. Patients also receive siltuximab IV over 1 hour on day 1 of each cycle prior to the administration of anti-PD1 or anti-PD-L1 therapy. Treatment repeats either every 3 weeks for up to 8 doses or every 4 weeks for up to 6 doses in the absence of disease progression or unacceptable toxicity. Patients may undergo biopsy and bone scan on study, as well as blood sample collection and CT or MRI throughout the study.

Who Is Running the Clinical Trial?

Yuanquan Yang

Lead Sponsor

Trials

2

Recruited

60+

Findings from Research

Siltuximab effectively blocks the IL-6/Stat3 signaling pathway in ovarian epithelial carcinoma, leading to reduced levels of phosphorylated Stat3 and anti-apoptotic proteins, which are often associated with cancer cell survival.

The treatment with siltuximab enhances the sensitivity of ovarian cancer cells to paclitaxel, significantly lowering the concentration needed to induce cell death, suggesting it may help overcome drug resistance in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer]. Guo, YQ., Lu, P., Duan, ZF., et al.[2017]

Siltuximab was approved by the FDA for treating multicentric Castleman disease (MCD) in HIV-negative and HHV-8-negative patients, based on a randomized trial with 79 patients showing a significant response rate; 34% of those treated with siltuximab achieved a durable tumor and symptomatic response compared to none in the placebo group.

The treatment was generally well-tolerated, with common side effects including pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections occurring in more than 10% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. Deisseroth, A., Ko, CW., Nie, L., et al.[2017]

Siltuximab, an anti-IL-6 monoclonal antibody, showed favorable preliminary safety in a study of 20 patients with early prostate cancer, with no adverse events related to the drug observed.

Treatment with siltuximab resulted in increased markers of cell proliferation and apoptosis, along with down-regulation of genes in the IL-6 signaling pathway, suggesting potential mechanisms for its therapeutic effects in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Karkera, J., Steiner, H., Li, W., et al.[2022]

Siltuximab, when combined with docetaxel, was found to be safe for patients with castration-resistant prostate cancer (CRPC), with only a few cases of dose-limiting toxicity reported among 39 patients in a phase 1 study.

The combination treatment showed promising efficacy, with 62% of patients achieving a significant decline in PSA levels, indicating a potential therapeutic benefit for CRPC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. Hudes, G., Tagawa, ST., Whang, YE., et al.[2021]

Siltuximab, an anti-IL-6 monoclonal antibody, was found to be well tolerated in patients with advanced solid tumors, with only one dose-limiting toxicity reported at 5.5 mg/kg and common adverse events including hepatic function abnormalities and fatigue.

Despite its safety profile, siltuximab showed no objective clinical responses in the treated solid tumors, with only 5 out of 84 patients achieving stable disease for more than 6 weeks, indicating limited efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Angevin, E., Tabernero, J., Elez, E., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer]. [2017]

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

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. [2017]

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

The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. [2022]

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

A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. [2021]

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

A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. [2022]