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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug siltuximab can prevent serious side effects when restarting immune therapy in people with advanced cancer. Immune therapy can enhance the body's ability to fight cancer but sometimes causes severe reactions. Siltuximab might reduce these reactions by calming the immune system. People with advanced cancer who previously experienced serious side effects from immune therapy and are considering restarting it might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that siltuximab is likely to be safe for humans?

Studies have shown that siltuximab is generally safe for people. In clinical trials, more than 10% of participants experienced rash and itchiness as the most common side effects. Research on patients with other conditions has shown that siltuximab does not cause serious problems with long-term use. This suggests it can be safely used over an extended period if needed.

For those considering joining a trial, these findings offer some reassurance about the safety of siltuximab. However, individual experiences may vary, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Siltuximab is unique because it targets the protein interleukin-6 (IL-6), which plays a crucial role in cancer-related inflammation and tumor growth. Unlike standard treatments that primarily focus on blocking PD-1 or PD-L1 proteins to boost the immune response against cancer, siltuximab works by directly interfering with the inflammatory processes that can promote cancer progression. Researchers are excited about this treatment because it offers a novel mechanism of action, potentially enhancing the effectiveness of traditional immunotherapies and providing another layer of attack against advanced cancers.

What evidence suggests that siltuximab might be an effective treatment for preventing severe irAEs in advanced cancer?

Research has shown that siltuximab yields promising results in cancer treatment. Studies indicate that siltuximab helps patients live longer without their cancer worsening and provides significant health benefits. Approximately 78% of patients experienced positive effects, and 52% saw their tumors shrink or disappear. Another study found that 73% of patients had a tumor response at higher doses. In this trial, participants will receive siltuximab combined with immune checkpoint inhibitors (either anti-PD1 or anti-PD-L1 antibodies), which may help manage side effects and improve outcomes in advanced cancer. ^{2 5 6 7 8}

Who Is on the Research Team?

Yuanquan Yang

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9631655/

Siltuximab is associated with improved progression-free ... Siltuximab treatment prolongs PFS, rapidly improves symptomatology, and provides meaningful clinical benefit despite some laboratory tests and enlarged lymph ...

2. member.myhealthtoolkitex.com member.myhealthtoolkitex.com/web/public/brands/medicalpolicy/external-policies/siltuximab-sylvant/

Siltuximab (Sylvant) A total of 18 (78%) of 23 patients (95% confidence intervals [CI]: 56% to 93%) achieved CBR and 12 patients (52%) demonstrated objective tumor response. All 11 ...

3. sylvant.com sylvant.com/hcp/efficacy-safety/

Efficacy & Safety SYLVANT met its primary endpoint of durable tumor and symptomatic response1,2. Durable tumor and symptomatic response with SYLVANT plus best supportive care ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4494175/

Siltuximab (CNTO 328): a promising option for human ... All eleven patients treated with the highest dose of 12 mg/kg achieved complete response, and eight patients (73%) achieved objective tumor response. The ...

5. aetna.com aetna.com/cpb/medical/data/800_899/0884.html

Siltuximab (Sylvant) - Medical Clinical Policy Bulletins Results showed 34 % of participants treated with Sylvant and BSC experienced tumor response, while no participant treated with placebo and BSC did. Common side ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4745809/

A phase 2, open-label, multicenter study of the long-term ... This preplanned safety analysis was conducted to evaluate the long-term safety of siltuximab treatment among 19 patients with MCD who had stable disease or ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32027862/

Long-term safety of siltuximab in patients with idiopathic ... These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e19586

Post hoc analysis of a long-term safety extension study Siltuximab led to sustained mean levels of CRP, Hb, ESR, fibrinogen, albumin, and platelet counts for the duration of the study. In the 19 ...