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.

• Authors: Mark A Schroeder, H Jean Khoury, Madan Jagasia, Haris Ali, Gary J Schiller, Karl Staser, Jaebok Choi, Leah Gehrs, Michael C Arbushites, Ying Yan, Peter Langmuir, Nithya Srinivas, Michael Pratta, Miguel-Angel Perales, Yi-Bin Chen, Gabrielle Meyers, John F DiPersio
• Journal: Blood advances (Blood Adv) Vol. 4 Issue 8 Pg. 1656-1669 (04 28 2020) ISSN: 2473-9537 [Electronic] United States
• PMID: 32324888 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Adrenal Cortex Hormones
• Protein Kinase Inhibitors
• Steroids
• JAK1 protein, human
• Janus Kinase 1

Topics

• Adolescent
• Adrenal Cortex Hormones
• Adult
• Graft vs Host Disease (drug therapy)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Janus Kinase 1
• Protein Kinase Inhibitors (adverse effects)
• Steroids