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Clinical Trial
. 2020 Apr 28;4(8):1656-1669.
doi: 10.1182/bloodadvances.2019001043.

V体育官网入口 - A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease

Mark A Schroeder  1 , H Jean Khoury  2 , Madan Jagasia  3 , Haris Ali  4 , Gary J Schiller  5 , Karl Staser  6 , Jaebok Choi  1 , Leah Gehrs  1 , Michael C Arbushites  7 , Ying Yan  7 , Peter Langmuir  7 , Nithya Srinivas  7 , Michael Pratta  7 , Miguel-Angel Perales  8 , Yi-Bin Chen  9 , Gabrielle Meyers  10 , John F DiPersio  1
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Clinical Trial

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

Mark A Schroeder et al. Blood Adv. .

"V体育官网" 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 VSports手机版. 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. .

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V体育官网 - Conflict of interest statement

Conflict-of-interest disclosure: M. A. S. received honoraria and research funding from Incyte Corporation. H. J. K. served on an advisory board and received research funding from Incyte Corporation. M. J. received research funding from Therakos, Janssen, and Incyte Corporation. H. A V体育ios版. and G. J. S. received research funding from Incyte Corporation. K. S. served as a consultant for RiverVest and Kinetic River and is a coinventor on a patent related to CART therapy. J. C. received honorarium from Incyte Corporation, received research funding from Mallinckrodt Pharmaceuticals, and served as a consultant for Daewoong Pharmaceutical. M. C. A. , Y. Y. , P. L. , N. S. , and M. P. are employees and stockholders of Incyte Corporation. M. -A. P. received honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte Corporation, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda; served on data and safety monitoring boards for Servier and Medigene; served on scientific advisory boards for MolMed and NexImmune; and has received research support for clinical trials from Incyte Corporation, Kite/Gilead, and Miltenyl Biotec. Y. -B. C. served as a consultant for Incyte Corporation and Takeda and received research funding from Incyte Corporation and Novartis Pharmaceuticals. J. F. D. served on advisory boards for Incyte Corporation, CellWorks, Macrogenics, Amphivena, Arch, Rivervest, and Bioline and is a cofounder of Magenta Therapeutics and WUGen. The remaining authors declare no competing financial interests.

Figures (V体育官网)

None
Graphical abstract
Figure 1.
Figure 1.
Duration of response. Duration of response is shown for individual patients with steroid-naive (n = 9 of 12 treated) (A) and steroid-refractory (n = 12 of 17 treated) (B) aGVHD at baseline.
Figure 2.
Figure 2.
PK of itacitinib on day 1 and day 7 stratified by concomitant CYP3A4 inhibitor use in relation to the concentration needed to inhibit IL-6- or TPO-induced STAT phosphorylation by 50%. Data are shown as mean ± standard error of the mean. *Only 6 patient samples were available for analysis at the first time point (baseline). IC50, half maximal inhibitory concentration; TPO, thrombopoietin.
Figure 3.
Figure 3.
Effects of itacitinib on T cells. Peripheral blood samples from serial time points from baseline through day 180 were analyzed (total samples: before treatment (Tx), n = 23; CR, n = 48; PR+MR, n = 47; NR+PD, n = 13). Patients who had both baseline and day 28 samples were evaluable for analysis of absolute change from baseline to day 28 (n = 18). Total CD4 count was not available for 1 patient at day 28, although data for activated CD4 cells were available for this patient. Only 2 nonresponders had evaluable samples at day 28. (A) Absolute peripheral blood CD4 and CD8 T-cell numbers following itacitinib treatment through day 180 by response and change over time at day 28. (B) CD4 and CD8 T-cell activation levels following itacitinib treatment through day 180 by response and change over time at day 28. (C) Overall and activated peripheral blood Treg levels following itacitinib treatment through day 180 by response and change over time at day 28. CR includes CR and VGPR. Pairwise comparison was assessed by Wilcoxon rank test. *P < .05 and **P < .01 vs before Tx, analysis of variance with Dunnett post hoc. HLADR, human leukocyte antigen D related; MR, mixed response; NR, no response; PD, progressive disease.
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References (V体育2025版)

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