First Line Therapy for High Risk Acute GVHD

Stem Cell Transplant Complications Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04061876
• Other study ID #: S2019-177-01
• Status: Completed
• Phase: Phase 2
• Start date: August 25, 2019
• Est. completion date: June 30, 2023

Study information

• Verified date: November 2023
• Source: Chinese PLA General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 )

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 198
• Est. completion date: June 30, 2023
• Est. primary completion date: August 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 65 Years

Eligibility

Inclusion Criteria:

1. diagnosed with hematological diseases.

2. 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.

3. 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:

1. recipients of second allogeneic stem cell transplant.

2. acute GVHD induced by donor lymphocyte infusion, interferon.

3. received first line aGVHD treatment before enrollment.

4. overlap GVHD syndrome.

5. pregnant or breast-feeding women.

6. absolute neutrophil count (ANC) <0.5×10e9/L or platelet count (PLT) < 20×10e9/L

7. Serum creatinine > 2.0 mg/dL or creatinine clearance < 40 mL/min measured or calculated by Cockroft-Gault equation.

8. uncontrolled infection

9. human immunodeficiency virus infection

10. active hepatitis b virus, hepatitis C virus infection and need antivirus treatment.

11. Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after the allo-HSCT was performed, or graft rejection.

12. allergic history to Janus kinase inhibitors.

13. 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.

14. Received Janus kinase inhibitor therapy after allo-HSCT for any indication.

15. 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.

Related Conditions & MeSH terms

• aGVHD
• Stem Cell Transplant Complications

Intervention

Drug:
• Ruxolitinib
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.
• Corticosteroid
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.

Locations

Country	Name	City	State
China	Chinese PLA General Hospital	Beijing	Beijing

Sponsors (6)

Lead Sponsor	Collaborator
Chinese PLA General Hospital	960th Hospital of PLA, Air Force Military Medical University, China, LU DAOPEI MEDICAL, The Second Affiliated Hospital of Dalian Medical University, The Second Hospital of Hebei Medical University

Country where clinical trial is conducted

China, 

References & Publications (5)

Kuzmina Z, Eder S, Bohm A, Pernicka E, Vormittag L, Kalhs P, Petkov V, Stary G, Nepp J, Knobler R, Just U, Krenn K, Worel N, Greinix HT. Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study. Leukemia. 2012 Apr;26(4):746-56. doi: 10.1038/leu.2011.257. Epub 2011 Sep 16. — View Citation

Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, Magenau J, Weisdorf DJ, Ho VT, Bolanos-Meade J, Alousi AM, Ferrara JL; Blood and Marrow Transplant Clinical Trials Network. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015 Jan;2(1):e21-9. doi: 10.1016/S2352-3026(14)00035-0. Epub 2014 Dec 23. — View Citation

Major-Monfried H, Renteria AS, Pawarode A, Reddy P, Ayuk F, Holler E, Efebera YA, Hogan WJ, Wolfl M, Qayed M, Hexner EO, Wudhikarn K, Ordemann R, Young R, Shah J, Hartwell MJ, Chaudhry MS, Aziz M, Etra A, Yanik GA, Kroger N, Weber D, Chen YB, Nakamura R, Rosler W, Kitko CL, Harris AC, Pulsipher M, Reshef R, Kowalyk S, Morales G, Torres I, Ozbek U, Ferrara JLM, Levine JE. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018 Jun 21;131(25):2846-2855. doi: 10.1182/blood-2018-01-822957. Epub 2018 Mar 15. — View Citation

Thepot S, Zhou J, Perrot A, Robin M, Xhaard A, de Latour RP, Ades L, Ribaud P, Petropoulou AD, Porcher R, Socie G. The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation. Leukemia. 2010 Nov;24(11):1852-8. doi: 10.1038/leu.2010.187. Epub 2010 Sep 9. — View Citation

von Bubnoff N, Ihorst G, Grishina O, Rothling N, Bertz H, Duyster J, Finke J, Zeiser R. 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). BMC Cancer. 2018 Nov 19;18(1):1132. doi: 10.1186/s12885-018-5045-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Nonrelapse mortality (NRM)	NRM was de?ned 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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