Siltuximab for the Prevention of Severe Immune-Related Adverse Events During Immune Checkpoint Inhibitor Rechallenge in Patients with Advanced Cancer, CIRES Trial

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 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