Reach-2 Trial Design: A Phase 3, Randomized, Open-Label, Multicenter Study to Evaluate Ruxolitinib Compared to Best Available Therapy in Patients with Corticosteroid-Refractory Acute Graft Vs Host Disease after Allogeneic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) serves to improve disease control and survival for patients with hematologic malignancies. However, success of allo-HSCT is limited by acute graft-versus-host disease (aGvHD). Among patients who develop grade II-IV aGvHD, ~ 30% to 50% of patients do not achieve sustained complete response (CR) to standard systemic corticosteroids. These steroid refractory aGvHD (SR-aGvHD) patients have an increased mortality risk, and treatment of SR-aGvHD is a significant unmet medical need. Based on retrospective data supporting treatment of SR-aGvHD with ruxolitinib (Zeiser R, et al. 2015), a global, multicenter, phase 3 registration study was developed. Methods: REACH-2 is a phase 3, randomized (1:1), open-label, multicenter study comparing ruxolitinib (10 mg twice daily) vs investigator-determined best available therapy (BAT) in patients with SR-aGvHD after allo-HSCT. Patients aged ≥ 12 years with clinically diagnosed grade II to IV SR-aGvHD with evidence of myeloid and platelet engraftment (absolute neutrophil count > 1000/mm3 and platelets ≥ 20000/mm3) are eligible for inclusion. Patients are excluded if they have received > 1 systemic treatment for SR-aGvHD, have clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features, have failed prior SCT < 6 months, or have an active uncontrolled infection (Figure 1). The primary objective is to compare the efficacy of ruxolitinib vs BAT as assessed by overall response rate (ORR) at day 28 of treatment. ORR is defined as the proportion of patients in each arm demonstrating a CR or partial response (PR) without requirement for additional systemic therapies for an earlier progression, mixed response, or nonresponse. The key secondary objective is to compare the rate of durable ORR at day 56 between ruxolitinib and BAT, defined as proportion of all patients in each arm who achieve a CR or PR at day 28 and maintain a CR or PR at day 56. Other secondary end points include ORR at day 14; duration of response: time from first response until aGvHD progression or the date of additional systemic therapies for aGvHD, for responders only; weekly cumulative steroid dose for each subject; overall survival, event-free survival, failure-free survival, non-relapse mortality, malignancy relapse/progression; incidence of cGvHD; pharmacokinetic parameters, exposure-efficacy relationship, patient-reported outcomes, and safety. Results/Conclusion: The REACH-2 registration trial has a target enrollment of 308 randomized patients. FPFV occurred in March 2017 and enrollment is ongoing. This trial was registered at ClinicalTrials.gov: NCT0291326.