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Abstract
Background Severe immune-related adverse events (irAEs) occur in 20–30% of patients, leading to discontinuation of immune checkpoint inhibitor (ICI)-based therapy.1–4 While some patients achieve long-term disease control, most eventually develop progressive disease and may benefit from ICI rechallenge. Upon rechallenging with ICI, about 30% of patients experience recurrent or de novo severe irAEs, with the highest risk in the first 6 months.4 The interleukin-6 (IL-6) pathway is crucial in irAE development.5 Clinically, IL-6 inhibitors successfully manage steroid-refractory severe irAEs like arthritis, colitis, and hepatitis.6 7 We hypothesize siltuximab, an anti-IL-6 antibody, prevents severe irAEs in ICI rechallenge.
Methods This Phase II trial is an open-label, single-center, single-arm study investigating the efficacy and safety of siltuximab prophylaxis in combination with ICI rechallenge (figure 1). Eligible patients with advanced cancers who have recovered from prior severe irAEs will receive siltuximab alongside standard-of-care anti-PD-1/PD-L1 therapy. Severe irAEs are defined as ≥ Grade 2 that necessitate stopping ICI and high-dose prednisone (≥0.5 mg/kg/day or equivalent). Depending on the interval of anti-PD-1/PD-L1 therapy, 40 patients will receive siltuximab at a dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks for up to 6 months with immunotherapy.
The primary endpoint is the rate of severe irAEs within the first 24 weeks of ICI rechallenge. We will use a Bayesian Optimal Phase II design with 74% power to detect an improvement in severe irAE rates from 30% to 15% at a one-sided significance level of 0.1, assuming a vague prior Beta (0.3,0.7) for the true toxicity rate to make a ‘go/no-go’ decision. The study will begin with a safety lead-in period, enrolling 6 patients for dose-limiting toxicity (DLT) evaluations. After confirming safety (≤ 2 DLTs), another 34 patients will be enrolled. Two planned interim analyses for futility will occur at 10 and 25 patients. If there are <3 severe irAEs among the first 10 patients, enrollment will continue. If there are <7 severe irAEs among the first 25 patients, the study will continue. When the number of evaluable patients reaches 40, we will reject the null hypothesis and conclude the treatment is acceptable if there are fewer than 9 severe irAEs (table 1).
Secondary endpoints include safety, objective responses, progression-free survival, and overall survival. Correlative studies will investigate IL-6-dependent and -independent biomarkers of irAEs in blood, tissue, and gut microbiome. Clinical trial information: NCT 06470971.
References
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Study Schema. Abbreviations: G = grade, irAE = immune-related adverse events, ORR = overall response rate, OS = overall survival, PFS = progression free survival
Stopping Criteria and Number of Patients Developing Severe irAE. Abbreviation: irAE = immune-related adverse events
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