Ruxolitinib In GvHD (RIG)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Drug: Experimental intervention; Drug: Standard treatment

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
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Dresden, Germany, 01307
    • Universitätsklinikum Dresden
  • Freiburg, Germany, 79106
    • University Medical Center
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg Eppendorf
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Köln, Germany, 50937
    • Universitatsklinikum Koln
  • Marburg, Germany, 35043
    • Universitätsklinikum Marburg
  • München, Germany, 81675
    • Universitätsklinikum München TU rechts der Isar
  • Würzburg, Germany, 97080
    • Universitatsklinikum Wurzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
efficacy of Ruxolitinib and BAT as compared to BAT alone 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	at day 28 after randomisation

Collaborators and Investigators

• Sponsor: Prof. Dr. Nikolas von Bubnoff
• Collaborators: Clinical Trials Unit Freiburg
• Investigators: Principal Investigator: Nikolas von Bubnoff, Professor, Medical Center - University of Freiburg

Publications and helpful links

General Publications

• 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.

Helpful Links

• BMC Cancer. 2018 Nov 19;18(1):1132. doi: 10.1186/s12885-018-5045-7

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2017
• Primary Completion (Actual): November 15, 2019
• Study Completion (Actual): November 15, 2019

Study Registration Dates

• First Submitted: March 10, 2015
• First Submitted That Met QC Criteria: March 23, 2015
• First Posted (Estimate): March 24, 2015

Study Record Updates

• Last Update Posted (Actual): December 2, 2019
• Last Update Submitted That Met QC Criteria: November 27, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Ruxolitinib; allogeneic stem cell transplantation; Graft-versus-Host Disease (GvHD); resistance to therapy
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: RIG-P000814; 2014-004267-20 (EudraCT Number); DRKS00007939 (Registry Identifier: DRKS)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No