Trial in Progress: A Phase 2, Single-Arm, Open-Label Study of Itacitinib (ITA) for the Prevention of Chimeric Antigen Receptor (CAR) T-Cell–Induced Cytokine Release Syndrome (CRS)

Abstract

<h3>Introduction</h3> Anti-CD19 CAR T cells have emerged as a powerful immunotherapeutic tool for treating B-cell malignancies. Tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) provided high durable response rates in pivotal trials and are approved by the FDA for treating relapsed/refractory B-cell malignancies. Despite impressive antitumor activity, CAR T therapy has unique toxicities. This includes CRS, a potentially life-threatening systemic inflammatory response affecting >50% of patients (pts) receiving tisa-cel or axi-cel with a range of clinical presentations and needs for intervention. Tocilizumab (TCZ; anti–IL-6R antibody) is approved for the treatment of severe or life-threatening CAR T–induced CRS. Although TCZ ± corticosteroids (CS) is effective in treating CRS, inpatient care is often required for close observation and CRS management adds significant costs to care. Additionally, TCZ- and CS-refractory CRS remains a challenge with poor outcomes. Therefore, preventing CRS vs treating established CRS may improve CAR T safety and expand access to pts who may not be otherwise eligible. Because several cytokines are involved in CRS pathogenesis, drugs blocking multiple inflammatory pathways may improve efficacy over IL-6 blockade alone. Furthermore, immune effector cell–associated neurotoxicity syndrome (ICANS), another common and potentially fatal side effect of CAR T therapy, does not respond to (and may be exacerbated by) TCZ. ITA is a potent and highly selective inhibitor of Janus kinase (JAK)-1, which mediates signaling of several inflammatory cytokines. In preclinical studies of CRS models, JAK1 inhibition with ITA significantly reduced serum levels of cytokines implicated in CRS, including IL-6, IL-12, and IFN-γ, without affecting antitumor activity of human CD19 CAR T cells in vivo, suggesting potential utility in the management of CRS. <h3>Objective</h3> To describe the study design of an ongoing trial investigating the safety and efficacy of ITA for the prevention of CRS in pts receiving CD19 CAR T cells. <h3>Methods</h3> Pts 12 years or older receiving axi-cel or tisa-cel for an approved hematologic malignant indication will be eligible for enrollment in this phase 2, single arm, open-label study. Approximately 62 pts will be treated (≥20 each to axi-cel and tisa-cel). Pts will receive an oral 200-mg dose of ITA once daily for ∼30 days (Day −3 to Day 26; CAR T infusion at Day 0; Figure 1). The primary endpoint is grade ≥2 CRS rate by Day 14; secondary endpoints include incidence and duration of any grade ICANS by Day 28, duration of all grades of CRS by Day 28, rates of any grade CRS 48 hours post–CAR T infusion and grade ≥2 CRS by Day 28, and safety of ITA. Objective response rate and measurable residual disease will also be evaluated. This study will examine safety and efficacy of ITA for prevention of CD19 CAR T–induced CRS while monitoring for effects on tumor response.