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Ruxolitinib In GvHD (RIG)

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ClinicalTrials.gov Identifier: NCT02396628
Recruitment Status : Recruiting
First Posted : March 24, 2015
Last Update Posted : November 27, 2018
Sponsor:
Collaborator:
Clinical Trials Unit Freiburg
Information provided by (Responsible Party):
Prof. Dr. Nikolas von Bubnoff, University Hospital Freiburg

Brief Summary:
The preliminary data demonstrate potent activity of Ruxolitinib in steroid-refractory aGvHD. In this phase 2 trial the efficacy of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD in approximately 12 transplantation centers in Germany will be compared. The response by monitoring the clinical GvHD grade, requirement of alternative GvHD active agents and serum levels of pro-inflammatory cytokines will be determined.

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Drug: Experimental intervention Drug: Standard treatment Phase 2

Detailed Description:

The pathophysiological hallmark of GvHD after allo-HCT is an allogeneic donor T cell re-sponse against recipient antigens. This process is aggravated by increased processing and presentation of host antigens by donor APCs following conditioning treatment. The al-logeneic T cell response leads to inflammation, tissue damage and fibrosis and is mediated by extensive production of inflammatory cytokines such as IL-1, IL-2R, IL-6 and TNF. The signal transmission of inflammatory cytokines in effector cells requires activation of specialized kinases from the family of the Janus kinases. These kinases, JAK1, 2 and 3 are linked to cytokine receptors, and are activated upon binding of the cytokine to the receptor of the inflammatory effector. The JAK1/2 kinase inhibitor Ruxolitinib (INC424) is approved for myelofibrosis. In advanced myelofibrosis, Ruxolitinib lead to sustained clinical remissions with regard to constitutional symptoms, weight loss and spleen size in the majority of treated patients. Of note, clinical responses correlated with a marked reduction in inflammatory plasma cytokines.

Importantly, cytokines down-regulated by Ruxolitinib in patients with myelofibrosis correspond to inflammatory effectors that mediate tissue damage and inflammation in GvHD. These are mainly the cytokines IL- 1, IL -6, TNF and IFN-gamma. Since Ruxolitinib suppresses the JAK1 / 2 cytokine response, we hypothesized that Ruxolitinib might attenuate the cytokine mediated inflammatory tissue damage in GVHD and thus might favourably affect the severity and course of GvHD after allo-HCT.

In vitro, we demonstrated in an allogeneic system (major mismatch mixed-lymphocyte reactions) that co-incubation with Ruxolitinib strongly suppressed both the proliferation of alloge-neic T cells and the production of inflammatory cytokines. Using a very aggressive major mismatch mouse model of acute GvHD Ruxolitinib treatment signifi-cantly prolonged survival of animals (see Figure 1A). In addition, in these animals showed a reduced weight loss, significantly reduced histopathological GvHD severity, suppression of inflammatory cytokines in the serum and a reduction of donor T cells in GvHD target organs such as the intestines.

Sole suppression of cytokine production or cytokine receptor activity by Ruxolitinib would be very similar to already established drugs for GvHD and no major conceptual advance. However we observed that Ruxolitinib did not only suppress cytokine production but also led to increased frequencies of FoxP3+ regulatory T cells. This cell type was previ-ously shown to lead to long-lasting tolerance as compared to the short-term immunosuppression achieved by conventional medication for GvHD.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicentre Phase 2 Trial to Evaluate the Efficacy of Ruxolitinib in Steroid-refractory Acute 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)
Actual Study Start Date : June 29, 2017
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Experimental intervention
Treatment with Ruxolitinib at a dose of 10 mg BID orally addition to BAT according DGHO-Onkopedia guidelines.
Drug: Experimental intervention
Treatment with Ruxolitinib at a dose of 10 mg BID orally addition to BAT according DGHO-Onkopedia guidelines

Active Comparator: Standard treatment
Treatment according to DGHO-Onkopedia guidelines for treatment of acute GvHD (as of March 2018). Optional cross over from BAT to Ruxolitinib and BAT in case of lack of response from day 28.
Drug: Standard treatment
Treatment according to DGHO-Onkopedia guidelines for treatment of acute GvHD (as of March 2018). Optional cross over from BAT to Ruxolitinib and BAT in case of lack of response from day 28.




Primary Outcome Measures :
  1. efficacy of Ruxolitinib and BAT as compared to BAT alone at day 28 after randomisation [ Time Frame: at day 28 after randomisation ]
    To evaluate efficacy of Ruxolitinib and BAT as compared to BAT alone at day 28 after randomisation start in steroid-refractory acute GvHD, measured as response rate



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Acute skin, intestinal (histologically confirmed) or liver GvHD > grade 1 according to standard criteria
  2. Age ≥18 years
  3. Failure of previous treatment, defined as presence of at least one of the following criteria:

    1. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least 2 mg/kg and lack of response after at least 7 days treatment
    2. Treatment with prednisone/prednisolone/methylprednisolone in a dose of at least 2 mg/kg and progression after at least 3 days of treatment
    3. Failure to taper the prednisone/prednisolone dose to <0.6 mg/kg/day or methylprednisolone dose to <0.5 mg/kg/day
  4. Written informed consent
  5. Ability to understand the nature of the study and the study related procedures and to comply with them

Exclusion Criteria:

  1. Uncontrolled underlying disease
  2. Active bleeding
  3. Absence of clinical signs of acute GvHD
  4. Diagnostic or distinctive clinical signs of chronic GvHD
  5. Uncontrolled bacterial, viral or fungal infection
  6. Absolute neutrophil count <0.5x103/µl
  7. Evidence of transplant-associated micrioangiopathy (TAM) (According to Jodele et al., 2015, diagnostic criteria for TAM)
  8. Any previous JAK2 inhibitor treatment prior to study enrolment, except Ruxolitinib given prior to the allogeneic stem cell transplantation
  9. Known Hypersensitivity to Ruxolitinib or any of the excipients
  10. Known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening.
  11. Female patients who are pregnant or breast feeding
  12. Concomitant use of any other investigational drug within the last thirty days before the start of this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02396628


Contacts
Contact: Nikolas von Bubnoff, Professor +49 761 270- ext 33210 nikolas.bubnoff@uniklinik-freiburg.de
Contact: Robert Zeiser, Professor +49 761 270- ext 36250 robert.zeiser@uniklinik-freiburg.de

Locations
Germany
Charité - Universitätsmedizin Berlin Recruiting
Berlin, Germany, 13353
Principal Investigator: Igor Blau, PD Dr.         
Sub-Investigator: Il-Kang Na, PD Dr.         
Sub-Investigator: Giang Lam Vuong, Dr.         
Universitätsklinikum Bonn Recruiting
Bonn, Germany, 53105
Principal Investigator: Dominik Wolf, Prof.         
Sub-Investigator: Karin Mayer, Dr.         
Universitätsklinikum Dresden Recruiting
Dresden, Germany, 01307
Principal Investigator: Friedrich Stölzel, Dr.         
Sub-Investigator: Rainer Ordemann, Prof.         
University Medical Center Recruiting
Freiburg, Germany, 79106
Contact: Nikolas von Bubnoff, Professor       nikolas.bubnoff@uniklinik-freiburg.de   
Principal Investigator: Nikolas von Bubnoff, Professor         
Sub-Investigator: Robert Zeiser, Professor         
Universitätsklinikum Hamburg Eppendorf Recruiting
Hamburg, Germany, 20246
Principal Investigator: Francis Ayuk, PD Dr.         
Sub-Investigator: Dietlinde Janson, Dr.         
Universitätsklinikum Heidelberg Recruiting
Heidelberg, Germany, 69120
Principal Investigator: Peter Dreger, Prof.         
Sub-Investigator: Thomas Luft, PD Dr.         
Universitätsklinikum des Saarlandes Recruiting
Homburg, Germany, 66421
Contact: Jörg T. Bittenbring, Dr.         
Principal Investigator: Jörg T. Bittenbring, Dr.         
Sub-Investigator: Niels Murawski, PD Dr.         
Universitätsklinikum Köln Recruiting
Köln, Germany, 50937
Contact: Udo Holtick, Dr.         
Principal Investigator: Udo Holtick, Dr.         
Sub-Investigator: Christof Scheid, Prof.         
Sub-Investigator: Marco Herling, Dr.         
Universitätsklinikum Marburg Recruiting
Marburg, Germany, 35043
Contact: Andreas Burchert, Prof.         
Principal Investigator: Andreas Burchert, Prof.         
Sub-Investigator: Kristina Sohlbach, Dr.         
Universitätsklinikum München TU rechts der Isar Recruiting
München, Germany, 81675
Principal Investigator: Mareike Verbeek, Dr.         
Sub-Investigator: Sandra Grass, Dr.         
Universitätsklinikum Würzburg Recruiting
Würzburg, Germany, 97080
Principal Investigator: Götz Grigoleit, Dr.         
Sub-Investigator: Sabrina Kraus, Dr.         
Sponsors and Collaborators
Prof. Dr. Nikolas von Bubnoff
Clinical Trials Unit Freiburg
Investigators
Principal Investigator: Nikolas von Bubnoff, Professor Medical Center - University of Freiburg

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof. Dr. Nikolas von Bubnoff, Coordinating Investigator, University Hospital Freiburg
ClinicalTrials.gov Identifier: NCT02396628     History of Changes
Other Study ID Numbers: RIG-P000814
2014-004267-20 ( EudraCT Number )
DRKS00007939 ( Registry Identifier: DRKS )
First Posted: March 24, 2015    Key Record Dates
Last Update Posted: November 27, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prof. Dr. Nikolas von Bubnoff, University Hospital Freiburg:
Graft-versus-Host Disease (GvHD)
resistance to therapy
allogeneic stem cell transplantation
Ruxolitinib

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases