Ruxolitinib for Steroid-refractory GVHD

Treatment of Steroid-refractory Acute and Chronic Graft-versus-host Disease With Inhibitor of Janus Kinases

Steroid-refractory acute GVHD (srGVHD) is one of the causes of mortality after allogeneic stem cell transplantation, while steroid-refractory chronic GVHD significantly increases morbidity, aggravates quality of life and may also impact survival. Currently there is no standard treatment of srGVHD. One of the most promising agents is Janus kinase (JAK) inhibitor ruxolitinib, which in the retrospective study demonstrated excellent response rate and survival of patients with either acute or chronic srGVHD. This study prospectively evaluates the efficacy of ruxolitinib in srGVHD patients.

Study Overview

• Status: Completed
• Conditions: Graft Vs Host Disease
• Intervention / Treatment: Drug: Ruxolitinib Oral Tablet

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Saint-Petersburg, Russian Federation, 197089
    • First Pavlov State Medical University of St. Petersburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of graft-versus-host disease established based on tissue biopsy
• Steroid-refractory acute or chronic graft-versus-host disease according to EBMT/ELN criteria (T. Ruutu et al, 2014)
• Age 1 to 70 years
• Karnofsky index >30%.
• Ability for oral drug intake
• Life expectancy > 1 month
• Signed informed consent

Exclusion Criteria:

• Severe organ dysfunction: AST or ALT >5 upper normal limits (excluding cases related to liver GVHD), creatinine >2 upper normal limits
• Requirement for vasopressor support at the time of enrollment
• Uncontrolled bacterial or fungal infection at the time of enrollment
• Pregnancy
• Somatic or psychiatric disorder making the patient (or legal guardian) unable to sign informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ruxolitinib treatment; Ruxolitinib 10 mg bid for adults and children with body weight > 40 kg, 0.15 mg/kg bid for children with body weight < 40 kg.

Drug: Ruxolitinib Oral Tablet; Dose reduction criteria for acute GVHD: grade 4 neutropenia or grade 4 thrombocytopenia related to ruxolitinib administration based on the decision of attending physician. Dose reduction criteria for chronic GVHD: grade 3 neutropenia, grade 3 thrombocytopenia or anemia requiring transfusion, related to ruxolitinib administration based on the decision of attending physician. Reduced dose schedule: 5 mg bid for adults and children with body weight > 40 kg, 0.08 mg/kg bid for children with body weight < 40 kg. Treatment discontinuation criteria: complete response; absence of response after 28 days or progressive disease after 7 days for acute GVHD; absence of response after 84 days or progressive disease after 28 days for chronic GVHD; life-threatening complications.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Partial response for acute GVHD is defined as the improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ. A response had to last for at least 3 weeks. Partial response for chronic GVHD was defined as reduction in GVHD National Institute of Health (NIH) severity score at east for one organ without deterioration in any other organ. A complete response was defined as the absence of any symptoms related to GVHD. Overall response is defined as presence of partial or complete response	84 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month overall survival	Time from start of ruxolitinib until death or 6 months, summarized using Kaplan-Meier estimates.	6 months
Toxicity based NCI CTC grades	Toxicity parameters based on NCI CTCAE 4.03 grades: nasea, vomiting, anemia, thrombocytopenia, leukopenia, neutropenia, hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), hemorrhagic cystitis (attending physician assessment).	6 months
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence		6 months
GVHD relapse incidence after complete response	Time from stopping ruxolitinib until recurrence of GVHD or 6 months, summarized using cumulative incidence estimates.	6 months
Relapse incidence of underlying hematologic malignancy	Time from starting ruxolitinib until hematologic relapse or 12 months, summarized using cumulative incidence estimates	12 months
Quality of life measured by FACT BMT ver. 4 questionnaire in adults		6 months
Quality of life measured by PedQL Stem Cell transplant module ver.1.0 questionnaire in children		6 months

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University
• Collaborators: Ministry of Health, Russian Federation
• Investigators: Study Director: Boris V Afanasyev, Prof, R.M.Gorbacheva Memorial Institute of Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University

Publications and helpful links

General Publications

• Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, Ajib S, de Fontbrune FS, Na IK, Penter L, Holtick U, Wolf D, Schuler E, Meyer E, Apostolova P, Bertz H, Marks R, Lubbert M, Wasch R, Scheid C, Stolzel F, Ordemann R, Bug G, Kobbe G, Negrin R, Brune M, Spyridonidis A, Schmitt-Graff A, van der Velden W, Huls G, Mielke S, Grigoleit GU, Kuball J, Flynn R, Ihorst G, Du J, Blazar BR, Arnold R, Kroger N, Passweg J, Halter J, Socie G, Beelen D, Peschel C, Neubauer A, Finke J, Duyster J, von Bubnoff N. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015 Oct;29(10):2062-8. doi: 10.1038/leu.2015.212. Epub 2015 Jul 31.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: December 14, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimate): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: ruxolitinib; JAK inhibitors; acute graft-versus-host disease; chronic graft-versus-host disease; Steroid-refractory GVHD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: 2016-29-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO