Clinical trial NCT02396628: Ruxolitinib In GvHD
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Graft vs Host Disease
Keywords: Graft-versus-Host Disease (GvHD)
resistance to therapy
allogeneic stem cell transplantation
Ruxolitinib
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
Collaborators: name: Clinical Trials Unit Freiburg
First posted: 2015-03-24
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: efficacy of Ruxolitinib and BAT as compared to BAT alone at day 28 after randomisation
timeFrame: at day 28 after randomisation
Secondary outcomes:
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Freiburg
country: Germany
facility: University Medical Center
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg
city: München
country: Germany
facility: Universitätsklinikum München TU rechts der Isar
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
Study officials:
affiliation: Medical Center - University of Freiburg
name: Nikolas von Bubnoff, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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.