Phase I Study of SHR0302, a Selective JAK1 Inhibitor, Combined with Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease after Allo-HSCT

Background: Chronic graft-versus-host-disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that affects various organs leading to a reduced quality of life, with an incidence of 40% to 70%. The standard first-line therapy for cGVHD is prednisone ± a calcineurin inhibitor, but most patients respond inadequately and prolonged corticosteroid use could cause a variety of side effects. SHR0302 is a Janus kinase (JAK) 1 selective inhibitor which has demonstrated efficacy in preclinical models of GVHD. Herein, we reported the safety and efficacy of SHR0302 plus prednisone as first-line treatment for newly diagnosed cGVHD after allo-SCT.

Methods: This was a phase I open-label study. Patients who were aged 18-70, and confirmedly diagnosed with first-episode moderate/severe cGVHD requiring systemic immunosuppressive therapy after allo-HSCT were included in the study. cGVHD was defined according to national institutes of health (NIH) criteria. Patients received SHR0302 plus prednisone daily. For each patient, prednisone was administered at an initial dose of 1 mg/kg/d for two weeks, then tapered according to the response of the patient. A 3 + 3 design was implemented for dose finding of SHR0302 at doses of 1mg/d, 2mg/d, 4mg/d, 6mg/d, and 8mg/d. The primary endpoints were safety and tolerability of the combination therapy of SHR0302 and prednisone assessed by NCI-CTCAE v5.0. And the secondary endpoints included the overall response rate (ORR) at week 4 of treatment and the recommended Phase II dose (RP2D). Dose-limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity or grade 3 non-hematologic toxicity associated with SHR0302 which occurred in the first 28 days of study treatment.

Results: As of July 30, 2022, 18 patients were enrolled in the study with 3 patients each in the dose level 1-4, and 6 patients in the dose level 5, with a median follow-up of 27 (4-91) weeks. The median age of the patients was 47 (31-64) years, of which 5 patients (27.8%) had moderate cGVHD, and 13 patients (72.2%) had severe cGVHD. The median cGVHD NIH score was 4 (3-7). The primarily affected organs were skin (61.1%) followed by liver (55.6%), and mouth (50.0%). As of data cutoff, only one patient (5.6%) discontinued therapy due to inadequate response.

No DLTs were seen in the first 4 dose levels. Only one DLT, grade ≥3 hypercholesterolemia, was observed among 6 patients who received 8mg/d of SHR0302. The patient who experienced DLT had preexisting hypercholesterolemia. A maximum tolerated dose was not reached. 17 patients (94.4%) experienced adverse events (AEs) related to SHR0302, and 4 patients (22.2%) experienced grade ≥3 AEs related to SHR0302. Hypercholesterolemia (61.1%), hypertriglyceridemia (44.4%), and platelet count decreased (33.3%) were the most common SHR0302 treatment-related AEs. No SHR0302 treatment-related serious adverse events were reported.

The ORR at week 4 after the first SHR0302 administration was 94.4%, including 4 patients (22.2%) achieving complete response, and 13 patients (72.2%) achieving partial response. Among 18 evaluable patients, only 1 patient treated at dose level 1 showed no response at week 4.

Conclusions: In summary, SHR0302 plus prednisone demonstrated encouraging efficacy with manageable toxicity in patients with steroid-naive cGVHD. Based on the results from the dose-escalation, 6-mg and 8-mg dose were selected for the dose-expansion.

No relevant conflicts of interest to declare.