Fecal Microbiota Transplantation With Ruxolitinib and Steroids as an Upfront Treatment of Severe Acute Intestinal GVHD (JAK-FMT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Intestinal GVHD
• Intervention / Treatment: Biological: allogeneic fecal microbiota; Drug: Ruxolitinib; Drug: Methylprednisone

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Oleg Goloshchapov; Phone Number: +79219792913; Email: golocht@yandex.ru
• Study Contact Backup: Name: Maksim Kucher, MD, PhD; Phone Number: +79219939902; Email: doctorkucher@yandex.ru

Study Locations

• Russian Federation
  • Saint Petersburg, Russian Federation, 197022
    • Recruiting
    • Pavlov First Saint-Petersburg State Medical University
    • Contact: Oleg Goloshchapov; Phone Number: +79219792913; Email: golocht@yandex.ru
    • Sub-Investigator: Alexey Chukhlovin, Professor
    • Sub-Investigator: Ivan Moiseev, PhD, MD
    • Sub-Investigator: Maksim Kucher, PhD, MD
    • Principal Investigator: Oleg Goloshchapov
    • Contact: Maksim Kucher, PhD, MD; Phone Number: +79219939902; Email: doctorkucher@yandex.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

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: FMT+ruxolitinib+steroids; ruxolitinib 10 mg bid, fecal microbiota transplantation 2 caps/kg single dose, methylprednisone 0.5 mg/kg bid

Biological: allogeneic fecal microbiota; 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.; Drug: Ruxolitinib; Ruxolitinib starting dose 10 mg bid. In case of grade 4 hematological toxicity dose can be reduced by 25-75%.; Drug: Methylprednisone; Methylprednisone starting dose 0.5 mg/kg bid IV or oral, with subsequent tapper by 0.1 mg/kg every 5 days.

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

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University
• Investigators: Principal Investigator: Boris Afanasyev, Professor, Pavlov First Saint-Petersburg State Medical University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: February 12, 2020
• First Submitted That Met QC Criteria: February 13, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: tfm-gvhd-2019

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