NCT07184853

Ruxolitinib Plus Etanercept vs Ruxolitinib for Steroid-Refractory Severe Acute GVHD

Prospective Multicenter Randomized Study of Ruxolitinib Plus Etanercept vs Ruxolitinib Alone for Corticosteroid-Refractory Severe Acute GVHD After Allogeneic HSCT

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 122 (estimated)
• Sponsor: First Affiliated Hospital of Zhejiang University · Academic / Other
• Sex: All
• Age: 12 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

This is a prospective, multicenter, randomized controlled trial designed to evaluate whether the combination of ruxolitinib and etanercept provides superior efficacy compared with ruxolitinib monotherapy in patients with severe corticosteroid-refractory acute graft-versus-host disease (SR-aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Acute graft-versus-host disease (aGVHD) is one of the most common and life-threatening complications following allo-HSCT. Although corticosteroids remain the standard first-line treatment, many patients do not respond adequately. For patients with severe steroid-refractory aGVHD, the prognosis is extremely poor, with high short-term mortality and very low long-term survival. Ruxolitinib, a JAK1/2 inhibitor, has been approved for the treatment of SR-aGVHD, but response rates remain suboptimal, particularly in patients with gastrointestinal involvement. Etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, has shown activity in GVHD by targeting inflammatory pathways. Previous observational studies from our center suggested that combining ruxolitinib with etanercept may improve response rates, especially in gastrointestinal and hepatic GVHD, without significantly increasing relapse risk. In this trial, approximately 122 patients with grade III-IV SR-aGVHD will be randomized 1:1 to receive either ruxolitinib alone or ruxolitinib plus etanercept. The primary endpoint is the overall response rate (ORR) at day 28. Secondary endpoints include durable response, best overall response, failure-free survival, overall survival, cumulative incidence of relapse, non-relapse mortality, incidence of chronic GVHD, and safety outcomes. This study seeks to provide new clinical evidence for an optimized treatment strategy for patients with severe SR-aGVHD, aiming to improve outcomes in this high-risk population.

Detailed description

Steroid-refractory severe acute graft-versus-host disease (SR-aGVHD) remains a leading cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Although ruxolitinib (JAK1/2 inhibition) improves outcomes versus best available therapy, non-response and limited durability-particularly with gastrointestinal involvement-underscore the need for rational combination strategies. Tumor necrosis factor-α (TNF-α) is a proximal driver of allo-inflammation; biomarker analyses suggesting elevated TNFR1 among non-responders to JAK inhibition support TNF-α pathway engagement as a potential mechanism of resistance. Prior single-arm, multicenter experience with ruxolitinib plus etanercept has shown encouraging activity in severe disease, including gastrointestinal and hepatic involvement, without an apparent increase in relapse risk, providing the rationale for this randomized evaluation. This prospective, multicenter, randomized, open-label study tests whether adding etanercept to ruxolitinib improves clinical response at the prespecified primary assessment time point in patients with corticosteroid-refractory severe aGVHD after allogeneic transplantation. Participants are randomized 1:1 to combination therapy or ruxolitinib alone, with stratification by baseline disease severity to balance key prognostic factors across arms. The open-label design reflects practical differences in administration; where feasible, centralized or blinded review procedures are implemented to mitigate assessment bias. Study treatment follows protocol-defined principles for initiation, modification, and discontinuation that align with current practice, including management algorithms for cytopenias, organ dysfunction, and relevant drug interactions. Systemic corticosteroids at enrollment are required for the SR definition; tapering after response is guided by predefined algorithms. Concomitant supportive care, infection prophylaxis, and transfusion support are provided according to institutional standards. Rescue therapy or treatment withdrawal is permitted under prespecified lack-of-benefit or safety criteria. The primary objective is to determine superiority of combination therapy over ruxolitinib alone on clinical response at the primary time point. Key secondary objectives address response durability, transplant-related outcomes, corticosteroid exposure, and safety/tolerability; exploratory analyses include infection burden and biomarker assessments to characterize pharmacodynamic effects and response heterogeneity. Outcome definitions and time frames are specified in the Outcome Measures section; eligibility criteria are provided in the Eligibility section. Safety is actively monitored throughout treatment and follow-up, with predefined surveillance for infections (including viral reactivation), cytopenias, and organ-specific toxicities. An independent safety review process periodically evaluates unblinded data per charter. The trial is sized to detect a clinically meaningful difference under conservative assumptions and includes longitudinal follow-up to capture durability, survival, and late safety signals, thereby informing whether dual pathway modulation (JAK and TNF-α) can improve outcomes in this high-risk population without unacceptable toxicity.

Conditions

• Graft vs Host Disease

Interventions

Type	Name	Description
DRUG	Ruxolitinib (JAKAVI®)	Ruxolitinib will be administered orally at a dose of 10 mg twice daily (approximately every 12 hours), with or without food. Dose modifications are allowed according to protocol-defined safety and efficacy criteria. Ruxolitinib may be continued for up to 24 weeks, with tapering guided by patient response and GVHD status.
DRUG	Etanercept (Enbrel)	Etanercept will be administered as a subcutaneous injection at a dose of 25 mg twice weekly for 4 weeks (total 8 doses). For patients with partial response at day 28, treatment may be extended once weekly for an additional 2-4 weeks at the investigator's discretion.

Timeline

• Start date: 2025-09-25
• Primary completion: 2027-09-25
• Completion: 2028-09-25
• First posted: 2025-09-22
• Last updated: 2025-09-22

Locations

1 site across 1 country: China