A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease

Abstract

Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

“…Itacitinib is a powerful anti JAK1 inhibitor that is effective in treating connective tissue diseases ( 116 ). In a phase-1 study on aGvHD, when administered at 200 or 300 mg, it induced 78.6% and 66.7% of overall response rate, respectively, with 70.6% of successes in steroid-refractory patients ( 117 ). On this basis, two studies trying itacitinib in cGvHD recently started the accrual (ClinicalTrials.gov identifier: NCT04200365, NCT03584516).…”

Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy

“…Similar to individuals experiencing CRS, animals receiving ConA have elevated serum levels of multiple inflammatory cytokines as well as behavioral changes such as fever, malaise, hypotension, hypoxia, capillary leak, multi-organ toxicity, and potentially death. To study the effect of itacitinib in this model, corresponding animals were prophylactically dosed with 60 or 120 mg/kg of itacitinib to achieve JAK1 inhibition coverage equivalent to that observed in clinical trials (27)(28)(29). When compared with vehicle-dosed animals, itacitinib was able to significantly reduce serum levels of many of the cytokines implicated in CRS (i.e., IL-6, IL-12, and IFN-) in a dose-dependent manner (Fig.…”

“Cytokine storm”, not only in COVID-19 patients. Mini-review

“…He supposed fedratinib suppresses TH-17 associated cytokine pathways (including the effect of IL-6 on cells) and so could prevent the harmful effect of TH17 associated cytokine storm. A recent study has been published (phase I) for itacitinib, selective JAK-1 inhibitor in GVHD [ 43 ]. At that stage, no information concerning cytokine release syndrome has been obtained.…”