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Donor Regulatory T Cells Infusion in Patients With Chronic Graft-versus-host Disease (GVHD)

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ClinicalTrials.gov Identifier: NCT01903473
Recruitment Status : Recruiting
First Posted : July 19, 2013
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Frédéric Baron, University of Liege

Brief Summary:

The immune system has offensive and defensive capacities. In bone marrow transplantation, offensive cells in the donor grafts may attack host's organs, leading to a complication known as Graft versus Host Disease (GVDH). At present, patients receive steroid treatment to combat this tricky situation. Nevertheless, some patients do not respond to this therapy. Recently, it has been shown that immune system cells having defensive capacities can help in preventing the occurrence of a GVDH.

This study aims to evaluate if these protective cells together with a non-standard immunosuppressor can improve the clinical condition and suppress the activity of the offensive cells in the graft.


Condition or disease Intervention/treatment Phase
Chronic Graft-Versus-Host Disease Acute Graft-Versus-Host Disease Steroid Refractory Graft-Versus-Host Disease Drug: Rapamycin Other: T regulatory cells Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

DTI arm

  • 10 patients will be included in the DTI (Treg) + IL-2 arm.
  • Treg infusion + rapa+ IL-2 will be considered safe if no patients die because of Treg infusion, less than 4 patients die of nonrelapse causes the first 90 days after inclusion in the study, and less than 4 patients experience chronic GVHD progression within the first 90 days after inclusion.
  • The study will be closed at any time a fourth patient experience nonrelapse mortality within 90 days of inclusion or experience GVHD progression within 90 days of inclusion.

Control arm

  • Up to 25 patients will be included in the control arm.
  • Rapa administration will be considered safe if less than 4/10, 8/20 or 10/25 patients die of nonrelapse causes the first 90 days after inclusion in the study and less than 4/10, 8/20 or 10/25 patients experienced chronic GVHD progression within the first 90 days after inclusion.
  • This arm of the study will be closed at any time the above criteria can no longer be met.
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Donor Regulatory T Cells (Treg) Infusion (DTI) in Patients With Steroid-refractory Chronic Graft-versus-host Disease (GVHD)
Study Start Date : July 2013
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : February 2022


Arm Intervention/treatment
Experimental: Donor Treg infusion arm
Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be first treated with Rapamycin while CNI (if any) will be discontinued and infused whith Treg cells 60-90 days after.
Other: T regulatory cells

One infusion of ≥ 0.5 x10E6 T reg cells/kg recipient at 60-90 days after first day of rapamycin administration and after calcineurin inhibitor discontinuation. The infusion procedure will take one hour.

Low-dose Il-2 (1x106 IU/day) will be started the day of DTI and will be continued for a period of 2months in order to expand infused donor Tregs.

Other Names:
  • T suppressor cells
  • Treg cells

Active Comparator: Control
Condition:Patients treated with steroids for a chronic GVHD occurring after allogeneic cell transplantation. Patients who have refractory chronic GVHD will be eligible. Patients in this arm will be treated with Rapamycin which is an alternative immunosupression strategy allowing to fight againt GVHD and CNI (if any) will be discontinued.
Drug: Rapamycin

Rapamycin will be started within 2 weeks after inclusion. Rapamycin will be given at 2-6 mg loading dose for one day, followed by approximately 1 mg daily to achieve a target trough level of 5 to 10 ng/mL. The frequency of trough level measurements will be done according to the investigator choice; Rapamycin may be discontinued in case of resolution of chronic GVHD ≥ 3 months or in case of un-manageable side effects or progression of chronic GVHD.

Calcineurin inhibitor discontinuation within 2 weeks after rapamycin initiation. No other modification of immunosuppressive drugs and in particular no decrease in the dose of steroids (unless necessary for side effects).

Other Name: Sirolimus




Primary Outcome Measures :
  1. To assess the safety of a combination of rapa administration, donor Treg infusion and low-dose IL-2 in patients with steroid-refractory chronic GVHD. [ Time Frame: 12 months after inclusion ]
    To assess the immunological changes (including Treg number/phenotype) occurring after donor Treg infusion and rapamycin administration. Treg will be defined as CD4+CD25+FoxP3+ T cells. Treg phenotype will include CD127, CD45RA, CCR4, CCR7 and KI67. Treg will also be assessed by an analysis of the methylation status of CpG dinucleotides located in a conserved region of FoxP3 intron 1.


Secondary Outcome Measures :
  1. To assess the efficiency of Treg selection with the Clinimacs procedure. [ Time Frame: 1 month after Treg selection ]
    Treg selection will be performed with the CliniMACS Miltenyi Biotec separation system using a two-step procedure: first, a CD8 and CD19 depletion, followed by CD25 positive selection.

  2. To assess the response rate of chronic GVHD (defined using the NIH criteria as defined by Lee et al.41) to donor Treg infusion + low-dose IL-2 + rapa at 1, 2, 3, 6 and 12 months after rapa onset. [ Time Frame: at 1, 2, 3, 6 and 12 months after rapamycin onset ]
    Using the NIH critera, the response rate of chronic GVHD will be evaluated.

  3. To compare response rate of chronic GVHD in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: at 1, 2, 3, 6 and 12 months after rapamycin onset ]
    Using the NIH critera, the response rate of chronic GVHD will be evaluated.

  4. To compare the incidence of viral, bacterial, fungal and parasital infection in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: over the 12 months of the trial ]
    Microbiology testing including standard virology and bacterial culture. In addition fungal and protozoal infections will be sought.

  5. To compare overall relapse incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: 1 year after rapamycin onset ]
  6. To compare overall survival incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: 1 year after rapamycin onset ]
  7. To compare overall progression-free survival incidence in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: 1 year after rapamycin onset ]
  8. To assess the impact of 8 weeks rapamycin administration on percentage and absolute counts of Treg and conventional T cells. [ Time Frame: 8 weeks after rapamycin onset ]
    Specific markers will allow to quantify Treg and conventional T cells

  9. To compare immunological changes in patients given Treg infusion + low-dose IL-2 + rapa (DTI arm) versus in those given rapa without Treg infusion (control arm; vide infra). [ Time Frame: Before DTI (day 21-28 after rapamycin onset). Week 1 and 3 after DTI (4-5 anf 6-7 weeks after rapamycin onset); month 3, 6 and 12 after rapamycin onset. ]
    The comparison will be performed on several sub-populations of CD4+ and CD8+ T cells as well as on various subset of B cells. In addition CMV-specific T cells will be compared between the two treatments.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

1. Patient criteria : Donor Treg infusion (DTI) and control arms.

  • Signed informed consent.
  • Grafts from HLA-identical siblings or HLA-matched unrelated donor (1 of 10 HLA-mismatch is allowed).
  • ≥ 18 years of age.
  • Steroid-refractory or steroid-resistant chronic GVHD defined as:

    • development of 1 or more new sites of disease while being treated for chronic GVHD,
    • progression of existing sites of disease while receiving treatment for chronic GVHD,
    • failure to improve despite at least 1 month of standard treatment for chronic GVHD.

or severe chronic GVHD and contra-indication to the use of steroids and at least failed one prior line of treatment.

  • Severe chronic GVHD according to NIH definition.
  • No prior failure of rapamycine as treatment for chronic GVHD
  • No contra-indication to the use of rapamycin.
  • No alemtuzumab administration in the last 6 months.
  • GFR > 25 mL/min.
  • No HIV seropositivity.
  • No fungal infection with radiological progression after treatment with amphotericine B or active azoles for > 1 month.
  • No other uncontrolled infection.
  • No progression of the hematological malignancy.
  • Karnofsky performance score ≥ 70%.
  • DLCO > 35% and no need of supplemental continuous oxygen.
  • No active post-transplant microangiopathy and no previous microangiopathy while on rapamycine.
  • No uncontrolled hypertriglyceridemia.

    2 Donor criteria : DTI arm only.

  • Donor ≥ 18 years of age.
  • Written informed consent to perform apheresis from the donor (all patients) and permission from the third party donor registry (in case of unrelated donor).
  • Standard criteria for leukapheresis and DLI following complete work-up according to standard procedures.

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): NCT01903473


Contacts
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Contact: Frédéric Baron, MD, PhD +3243667201 F.Baron@chu.ulg.ac.be
Contact: Yves Beguin, MD, PhD +3243667201 yves.beguin@chu.ulg.ac.be

Locations
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Belgium
Katholieke Universiteit Leuven Recruiting
Leuven, Vlaams-Brabant, Belgium, 3000
Contact: Hélène Schoemans, MD    +3216346889    helene.schoemans@uzleuven.be   
Contact: Johan Maertens, MD, PhD    +3216346889    johan.maertens@uzleuven.be   
Principal Investigator: Hélène Schoemans, MD         
Sub-Investigator: Johan Maertens, MD, PhD         
University Hospital Liège Recruiting
Liège, Belgium, 4000
Contact: Frédéric Baron, MD, PhD    +3243667201    f.baron@ulg.ac.be   
Contact: Yves Beguin, MD, PhD    +3243667201    yves.beguin@chu.ulg.ac.be   
Principal Investigator: Frédéric Baron, MD, PhD         
Sub-Investigator: Yves Beguin, MD, PhD         
Sub-Investigator: Evelyne Willems, MD, PhD         
Sub-Investigator: Etienne Baudoux, MD         
Sub-Investigator: Chantal Lechanteur, PhD         
Sub-Investigator: Alexandre Carpentier, PhD         
Sub-Investigator: Stéphanie Humblet-Baron, PhD         
Sub-Investigator: Muriel Hannon         
Sponsors and Collaborators
University of Liege
Investigators
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Principal Investigator: Frédéric Baron, MD, PhD CHU-ULg

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Responsible Party: Frédéric Baron, MD, PhD, University of Liege
ClinicalTrials.gov Identifier: NCT01903473     History of Changes
Other Study ID Numbers: TJB1117
First Posted: July 19, 2013    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019

Keywords provided by Frédéric Baron, University of Liege:
Allogeneic hematopoietic cell transplantation
GVHD
Regulatory T cells
Steroid refractory
Rapamycin
Immune recovery
Infusion
HLA-identical sibling
HLA-matched unrelated donor
IL-2

Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Sirolimus
Everolimus
Calcineurin Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action