First Line Therapy for High Risk Acute GVHD

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of combined Ruxolitinib With Corticosteroids as First Line Therapy for the Treatment of High risk aGVHD(acute graft-versus-host disease )

Detailed Description
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Acute graft-versus-host disease (aGVHD) is treated with systemic corticosteroid immunosuppression as first line therapy. Many patients with high risk aGVHD do not respond to primary therapy, high-dose systemic corticosteroids; therefore, survival for those patients remains particularly poor. Here we determine the efficacy and safety of combined Ruxolitinib With Corticosteroids as First Line Therapy for the Treatment of High risk aGVHD.

Official Title
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Ruxolitinib in Combination With Corticosteroid as First Line Therapy for the Treatment of High Risk Acute Graft-Versus-Host Disease

Conditions
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aGVHD, Stem Cell Transplant Complications

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosed with hematological diseases. Have undergone first allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies. new onset of grade II IV aGVHD or intermediate or high risk aGVHD (based on ST2, REG3a, other experimental objects) within 100 days post-transplantation. Exclusion Criteria: recipients of second allogeneic stem cell transplant. acute GVHD induced by donor lymphocyte infusion, interferon. received first line aGVHD treatment before enrollment. overlap GVHD syndrome. pregnant or breast-feeding women. absolute neutrophil count (ANC) <0.5×10e9/L or platelet count (PLT) < 20×10e9/L Serum creatinine > 2.0 mg/dL or creatinine clearance < 40 mL/min measured or calculated by Cockroft-Gault equation. uncontrolled infection human immunodeficiency virus infection active hepatitis b virus, hepatitis C virus infection and need antivirus treatment. Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after the allo-HSCT was performed, or graft rejection. allergic history to Janus kinase inhibitors. Severe organ dysfunction unrelated to underlying GVHD, including: Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction). Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy. Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen. Received Janus kinase inhibitor therapy after allo-HSCT for any indication. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib combined with Corticosteroids<br>Participants began oral administration of ruxolitinib at 5 mg QD; Methylprednisolone: 1mg/kg/d , iv or iv gtt for at leas 5 days, then taper according to the clinical response. | Drug: Ruxolitinib<br>* Participants began oral administration of ruxolitinib at 5 mg QD;Methylprednisolone: 1mg/kg/d , iv or iv gtt for at least 5 days, then taper according to the clinical response.<br>* Other names: New;Drug: Corticosteroid<br>* Methylprednisolone: 2mg/kg/d , iv or iv gtt for at least 3 days, then taper according to the clinical response. 1mg/kg/d , iv or iv gtt for at least 5 days, then taper according to the clinical response.<br>* Other names: Traditional;|
| Active Comparator: Corticosteroids<br>Methylprednisolone: 2mg/kg/d , iv or iv gtt for at least 1 week, then taper according to the clinical response. | Drug: Corticosteroid<br>* Methylprednisolone: 2mg/kg/d , iv or iv gtt for at least 3 days, then taper according to the clinical response. 1mg/kg/d , iv or iv gtt for at least 5 days, then taper according to the clinical response.<br>* Other names: Traditional;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) at Day 28 | Defined as the proportion of participants demonstrating a complete response (CR), or partial response (PR). | Day 28 after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-month duration of response | Defined as the time from first response until graft-versus-host disease (GVHD) progression or death. Six-month duration of response will be assessed when all participants who are still on study complete the Day 180 visit. | Six-month after treatment | 
| Duration of response | Defined as the time from first response until GVHD progression or death, when all participants who are still on study complete the Day 90 visit. | Day 90 after treatment | 
| Nonrelapse mortality (NRM) | NRM was deﬁned as death from any cause without relapse. Cumulative incidence of NRM was analyzed in a competing risk framework using Gray's method. | 2 years after treatment | 
| Relapse rate | Defined as the proportion of participants whose underlying malignancy relapsed.Relapse was defined as hematologic recurrence of malignancies after transplantation. Cumulative incidence of relapse was analyzed in a competing risk framework using Gray's method. | 2 years after treatment | 
| Disease-free survival (DFS) | Defined as the time from first dose of ruxolitinib to the earliest date that a participant died, had a relapse/progression of the underlying malignancy, required additional therapy for aGVHD, or demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD).DFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization. | 2 years after treatment | 
| Overall survival (OS) | Defined as the time from study enrollment (first day of ruxolitinib treatment) to death due to any cause. OS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization. | 2 years after treatment | 
| GVHD-free and relapse-free survival (GRFS) | GRFS was defined as the time onset of grade 3 to 4 aGVHD, moderate to severe cGVHD, or relapse/disease progression/death. GRFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization. | 2 years after treatment | 
| recurrence of aGVHD | Defined as the proportion of participants whose aGVHD relapsed.Relapse was defined as recurrence of new GVHD related symptoms after complete remission of aGVHD. Cumulative incidence of recurrence of aGVHD was analyzed in a competing risk framework using Gray's method. | 1 years after treatment | 
| Failure-free survival | Failure-free survival (FFS) refers to the time from randomization to disease relapse or progression, non-relapse mortality, or the addition of new therapy for aGVHD. | 2 years after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aGVHD