Fecal Microbiota Transplantation With Ruxolitinib and Steroids as an Upfront Treatment of Severe Acute Intestinal GVHD

Study Overview
=================
Brief Summary
-----------------
Therapy of severe intestinal graft-versus-host disease (GVHD) despite the introduction of novel target agents is associated with worse outcome compared to the other forms. Response to steroids is observed only in about 10% of patients. The most promising approaches are JAK inhibition and fecal microbiota transplantation. In this pilot study we evaluate this combination treatment in the first line.

Detailed Description
-----------------
Acute intestinal GVHD grade III-IV after allogeneic stem cell transplantation the form with low effectiveness of corticosteroids. Despite high response rate to systemic immunosupressive agents, long term survival in this group is poor due to recurrent septic episodes and gut colonization with multidrug resistant bacteria. Fecal microbiota transplantation (FMT) from a healthy allogeneic donor, allows to restore numerous local and systemic microbiota functions, including immunomodulation and thus to reduce/stop the manifestations of GVHD. The therapeutic mechanism of action of FMT is based on competition for nutrients between obligate and pathologic bacterial strains, direct growth inhibition of the pathological pathogens, host immune system modulation, especially T-reg homeostasis, through interaction with the normal microbiota.In this pilot trial we combine FMT with ruxolitinib and steroids, one of the most effective option for refractory GVHD.

Official Title
-----------------
Pilot Study of Fecal Microbiota Transplantation in Combination With Ruxolitinib and Steroids for Severe Acute Intestinal Graft-versus-host-disease After Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
-----------------
Intestinal GVHD

Intervention / Treatment
-----------------
* Biological: allogeneic fecal microbiota
* Drug: Ruxolitinib
* Drug: Methylprednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 5-70 years Histologically confirmed gastrointestinal acute GVHD Grade III-IV gastrointestinal GVHD based on 2016 MAGIC criteria Ability for oral drug intake Signed informed consent Exclusion Criteria: Requirement for oxigen and/or vasopressor support Respiratory distress >grade I Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits,creatinine clearance < 60 mL/min Ongoing fluconazole therapy Any malignancy requiring systemic therapy at the time of enrollment Mixed chimerism at last evaluation Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky index <30% Severe concurrent illness that can interfere with study procedures Somatic or psychiatric disorder making the patient unable to sign informed consent
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FMT+ruxolitinib+steroids<br>ruxolitinib 10 mg bid, fecal microbiota transplantation 2 caps/kg single dose, methylprednisone 0.5 mg/kg bid | Biological: allogeneic fecal microbiota<br>* Single dose of capsules with fecal transplant (capsules for adults - 400-815mg, for adolescents - 280-500mg, for children - 160-320mg) - 2 capsules/kg body weight, divided in two consecutive days Additional supportive therapy after FMT include omeprazole 40mg po, inulin 1gr x 4 times a day po, metoclopramide 40mg po.<br>Drug: Ruxolitinib<br>* Ruxolitinib starting dose 10 mg bid. In case of grade 4 hematological toxicity dose can be reduced by 25-75%.<br>Drug: Methylprednisone<br>* Methylprednisone starting dose 0.5 mg/kg bid IV or oral, with subsequent tapper by 0.1 mg/kg every 5 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from treatment initiation to death or end of follow up | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overal response rate | Evaluated with 2009 consensus criteria and 2016 severity grading on days +7,+28, +56, +100 | 100 days | 
| Incidence of Adverse Events based on CTC AE 5.0 | Based on CTC AE 5.0 | 100 days | 
| Infectious complications | Cumulative incidence of bacterial, viral and fungal infections | 100 days | 
| Time to steroid discontinuation | Time from treatment initiation to steroid cessation without GVHD flare | 100 days | 
| Time to ruxolitinib discontinuation | Time from treatment initiation to ruxolitinib cessation without GVHD flare | 365 days | 
| Time to systemic immunosuppression discontinuation | Time from treatment initiation to cessation of all systemic immunosupression without GVHD flare | 365 days |