Using siltuximab to prevent severe side effects during cancer treatment

Immune Checkpoint Inhibitor Rechallenge in Combination With Siltuximab Prophylaxis for Patients Who Had Prior Immune-Related Adverse Event (CIRES Trial)

This study is testing if the drug siltuximab can help prevent severe side effects in cancer patients who are getting immune therapy again.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 40 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Ohio State University Comprehensive Cancer Center (Academic / other)
• Drugs / interventions: radiation, prednisone, siltuximab
• Locations: 1 site (Columbus, Ohio)
• Trial ID: NCT06470971 on ClinicalTrials.gov

What this trial studies

This phase II trial investigates the effectiveness of siltuximab in preventing severe immune-related adverse events (irAEs) during the rechallenge of immune checkpoint inhibitors (ICIs) in patients with advanced cancer. The study aims to determine if siltuximab can reduce the occurrence of new or recurring severe irAEs within 24 weeks of ICI therapy. Additionally, it will assess the preliminary anti-tumor activity of this combination and explore potential predictive biomarkers and patient-reported outcomes. Patients will receive siltuximab alongside anti-PD1 or anti-PD-L1 therapy, with treatment cycles lasting up to 8 doses.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with advanced cancer who have previously experienced severe irAEs during ICI therapy.

Not a fit: Patients who have not experienced severe irAEs during prior ICI therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly enhance the safety and tolerability of immune checkpoint inhibitor therapy for patients with advanced cancer.

How similar studies have performed: While the use of siltuximab in this context is novel, other studies have explored similar approaches with immune checkpoint inhibitors, indicating potential for success.

Eligibility criteria

Inclusion Criteria:

* Males or females aged ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
* Patients with any advanced cancer types who would benefit from anti-PD1 or anti-PD-L1 therapy rechallenge at the investigator's discretion
* Patients must have had prior severe irAE while on ICI monotherapy or in combination with other anticancer treatment. Severe irAE is defined as any grade 2 or higher irAE requiring treatment discontinuation and prednisone \> 0.5 milligrams (mg)/kilogram (kg)/day (or equivalent) followed by a taper ≥ 4 weeks. Patients with history of grade 4 severe irAE need to carefully weigh the risks and benefits and might be eligible on a case-by-case basis after discussion with principal investigator (PI)
* Recovery from prior irAEs to ≤ grade 1
* Patients who are on prednisone ≤ 10 mg/day (d) or equivalent are allowed
* Hemoglobin \> 7 g/dL and \< 17 g/dL
* Absolute neutrophil count (ANC) ≥ 1000 per mm\^3
* Platelet count ≥ 75 × 10\^9/L
* Serum bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN or ≤ 5 × ULN for patients with liver metastases
* Measured or calculated creatinine clearance (CL) ≥ 30 mL/min except patients with end-stage renal disease on hemodialysis
* Cycle 1 day 1 of the study treatment should be at least 2 weeks since prior systemic therapy, radiotherapy, or surgery
* Estimated life expectancy, in the judgment of the investigator, of at least 12 weeks
* Subjects of childbearing potential must have a negative serum pregnancy test at screening
* Subjects of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception (i.e., less than 1% failure rate), from the time of signing informed consent and for the duration of study participation through 3 months following the last dose of study drug

  * Childbearing potential is defined by the following criteria: 1. Subject has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  * Highly effective birth control methods (less than 1% failure rate per year if used consistently and correctly) include but are not limited to: 1. Oral, injected, or implanted hormonal method of contraception; 2. Place of intrauterine device (IUD) or system (IUS); 3. Tubal ligation (tubes tied) or a sterile partner (effective bilateral vasectomy)
* Subjects must not breastfeed a child during the study and for 3 months after the last dose of study drug
* Ability to understand and willingness to sign the written informed consent document

Exclusion Criteria:

* Women who are pregnant or breastfeeding
* Any ≥ grade 3 irAEs in which the risks outweigh the benefits per investigator's discretion (these may include but are not limited to myocarditis, myasthenia gravis, Guillain-Barré syndrome, encephalitis, myelitis, or other life-threatening events)
* Has active autoimmune disease or irAE requiring systemic treatment with steroids (\> 10 mg daily doses of prednisone or equivalent) or other immunosuppressive agents or any condition that, in the investigator's judgment, precludes treatment with anti-PD-1/PD-L1 therapy
* Cycle 1 day 1 of the study treatment must be at least 2 weeks beyond high dose systemic corticosteroids (prednisone \> 0.5 mg/kg/day or equivalent); chronic steroid use up to 10 mg daily prednisone (or equivalent) is permitted
* Other concurrent anticancer therapy except for palliative radiation and hormone therapy
* Has a known history of HIV-1/2 with detectable viral load and/or CD4 (cluster of differentiation 4) count \< 300/mL within the previous 3 months
* Has detectable hepatitis B virus (HBV) or hepatitis C virus (HCV) viral load polymerase chain reaction (PCR) if there is a known history of active hepatitis B or hepatitis C
* 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
* Presence of a transplanted solid organ (with the exception of a corneal transplant more than 3 months prior to screening) or having received an allogeneic bone marrow transplant or an allogeneic peripheral blood stem cell transplant
* Uncontrolled concomitant illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association \[NYHA\] class III or IV), unstable angina pectoris, myocardial infarction within 1 month prior to enrollment, uncontrolled cardiac arrhythmias, uncontrolled seizures, or severe noncompensated hypertension (systolic blood pressure \> 180mmHg or diastolic blood pressure \> 120mmHg)
* Patients with a current severe infection
* Known unmanageable allergies, hypersensitivity, intolerance to monoclonal antibodies, to murine, chimeric, human proteins or their excipients
* Prior failure of interleukin-6 or interleukin-6 receptor targeted therapies. Prior IL-6 or IL-6 receptor-targeted therapies are permitted if the response was favorable
* Received any investigational drug within 30 days

Where this trial is running

Columbus, Ohio

• Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States (Recruiting)

Study contacts

• Principal investigator: Yuanquan Yang, MD, PhD — Ohio State University Comprehensive Cancer Center
• Study coordinator: The Ohio State University Comprehensive Cancer Cener

Conditions Advanced Malignant Solid Neoplasm; Hematopoietic and Lymphatic System Neoplasm