Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628)

Abstract

BackgroundGraft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD.MethodsThe RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers.DiscussionThis randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur.Trial registrationNCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5045-7) contains supplementary material, which is available to authorized users.

IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

“…A recent study reported that use of ruxolitinib caused more severe cytopenia in children, who in general have better thymus function compared with adults [39]. This relationship could be important as ruxolitinib was recently approved to treat acute GVHD in humans [40,41].…”

Treatment and unmet needs in steroid-refractory acute graft-versus-host disease

“…Ruxolitinib is also being assessed in the REACH2 study (NCT02913261), an open-label, multicenter, phase 3 crossover study comparing ruxolitinib with best available treatment (BAT) for SR-aGVHD; the study met its primary endpoint of ORR at day 28 [78,85]. The third study, Ruxolitinib in GVHD (RIG; NCT02396628), is an open-label, multicenter, prospective, randomized, phase 2 study comparing the efficacy of ruxolitinib plus BAT vs BAT in SR-aGVHD [86].…”

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

“…In 2014, ruxolitinib was further approved for the treatment of polycythemia vera (PV) [ 29 ]. The drug was also recently evaluated in a phase 2 trial for its activity in graft-versus-host-disease (GvHD) [ 30 , 31 ].…”