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A Phase 1/2 Trial of Donor Regulatory T-cells for Steroid-Refractory Chronic Graft-versus-Host-Disease (TREGeneration)

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ClinicalTrials.gov Identifier: NCT02385019
Recruitment Status : Recruiting
First Posted : March 11, 2015
Last Update Posted : March 6, 2018
Sponsor:
Collaborators:
Hospital de Santa Maria, Portugal
IPOFG Lisboa, Portugal
IPOFG Porto, Portugal
Information provided by (Responsible Party):
Joao F. Lacerda, Instituto de Medicina Molecular João Lobo Antunes

Brief Summary:
Phase 1/2 clinical study for the treatment of steroid-refractory chronic graft versus host disease after an allogeneic transplant of hematopoietic progenitors with donor CliniMACS-selected regulatory T cells

Condition or disease Intervention/treatment Phase
Graft vs Host Disease Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease Phase 1 Phase 2

Detailed Description:

Phase 1/2 clinical study evaluating safety (Phase 1) and preliminary efficacy (Phase 2) of donor regulatory T cells for patients with steroid-refractory chronic graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).

Patients must have persistent signs and symptoms despite the use of prednisone or equivalent at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day), for at least 4 weeks without complete resolution of signs and symptoms. Occasional patients requiring lower doses of prednisone will be eligible if associated with other immunosuppressive drugs.

Phase 1 clinical trial will include groups of 5 patients sequentially treated with: 0.5 x 10ˆ6, 1.0 x 10ˆ6, 2-3 x 10ˆ6 donor Treg/kg. Phase 2 clinical trial will include another 5 to 10 patients treated with MTD.

Donor Treg will be selected by the following sequential steps:

  1. - negative depletion of CD8 and CD19 cells
  2. - positive selection of CD25 cells

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of Donor Regulatory T-cells for Steroid-Refractory Chronic Graft-versus-Host-Disease
Study Start Date : March 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Administration of 0.5 x 10ˆ6 donor Treg/kg
First group of 5 patients will receive a total of 0.5 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.
Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

Regulatory T cells selected by a sequential 2 step procedure:

  1. - Negative selection of CD8 and CD19 cells
  2. - Positive selection of CD25 cells

Experimental: Administration of 1.0 x 10ˆ6 donor Treg/kg
Second group of 5 patients will receive a total of 1.0 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.
Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

Regulatory T cells selected by a sequential 2 step procedure:

  1. - Negative selection of CD8 and CD19 cells
  2. - Positive selection of CD25 cells

Experimental: Administration of 2.0-3.0 x 10ˆ6 donor Treg/kg
Third group of 5 patients will receive a total of 2.0-3.0 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.
Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

Regulatory T cells selected by a sequential 2 step procedure:

  1. - Negative selection of CD8 and CD19 cells
  2. - Positive selection of CD25 cells

Experimental: Administration of MTD of donor T reg
Preliminary Phase 2 study will include another 5 to 10 patients at the MTD identified in the Phase 1 study
Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

Regulatory T cells selected by a sequential 2 step procedure:

  1. - Negative selection of CD8 and CD19 cells
  2. - Positive selection of CD25 cells




Primary Outcome Measures :
  1. Progression of graft versus host disease according to the 2014 NIH consensus criteria and myelosuppression after the administration of 3 doses of donor regulatory T cells / kg recipient's body weight: 0.5 x 10ˆ6, 1.0 x 10ˆ6 and 2.0-3.0 x 10ˆ6 cells [ Time Frame: Response evaluated 12 weeks after infusion ]
    Progression of graft versus host disease and myelosuppression are indicators of toxicity and MTD associated with the infusion of donor regulatory T cells


Secondary Outcome Measures :
  1. Chronic graft versus host disease improvement according to the 2014 NIH consensus criteria following the infusion of donor regulatory T cells [ Time Frame: Response evaluated 12 weeks after infusion ]
  2. Total lymphocyte, CD4, CD8 and regulatory T cell counts after the infusion of donor regulatory T cells for the treatment of chronic graft versus host disease [ Time Frame: Response evaluated 12 weeks after infusion ]
  3. Survival at 1 year after administration of donor regulatory T cells in patients with chronic graft versus host disease [ Time Frame: Response evaluated 12 months after infusion ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Patients must have persistent signs and symptoms despite the use of prednisone or equivalent at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day), for at least 4 weeks without complete resolution of signs and symptoms. Occasional patients requiring lower doses of prednisone will be eligible if associated with other immunosuppressive drugs.
  2. Stable immunosuppressive medication in the 4 weeks prior to initiation of treatment
  3. PS 0-2 ECOG
  4. Adequate liver, kidney, lung and hematopoietic system functions

Exclusion Criteria:

  1. Pediatric patients
  2. Pregnant women
  3. Ongoing prednisone requirement >1 mg/kg/day (or equivalent)
  4. Concurrent use of calcineurin-inhibitor plus sirolimus (either agent alone is acceptable)
  5. New immunosuppressive medication in the 4 weeks prior
  6. Extra-corporeal Photopheresis or rituximab therapy in the 4 weeks prior
  7. Exposure to T-cell or IL-2 targeted medication (e.g. ATG, alemtuzumab, basiliximab, denileukin diftitox) within 100 days prior
  8. Donor lymphocyte infusion within 100 days prior
  9. Active malignant relapse
  10. Active uncontrolled infection
  11. HIV-infected patients

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): NCT02385019


Locations
Portugal
Instituto Portugues de Oncologia Recruiting
Lisboa, Portugal, 1099-023
Contact: Isabelina Ferreira, MD    +351917502335    iferreira@ipolisboa.min-saude.pt   
Hospital de Santa Maria, Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular Recruiting
Lisboa, Portugal, 1649-028
Contact: Joao F Lacerda, MD PhD    +351919727656    jlacerda@fm.ul.pt   
Instituto Portugues de Oncologia Recruiting
Porto, Portugal, 4200-072
Contact: Carlos Pinho Vaz, MD    +351968014520    cpvaz@ipoporto.min-saude.pt   
Sponsors and Collaborators
Instituto de Medicina Molecular João Lobo Antunes
Hospital de Santa Maria, Portugal
IPOFG Lisboa, Portugal
IPOFG Porto, Portugal

Responsible Party: Joao F. Lacerda, MD PhD, Associate Professor of Medicine, Instituto de Medicina Molecular João Lobo Antunes
ClinicalTrials.gov Identifier: NCT02385019     History of Changes
Other Study ID Numbers: TREGeneration-Portugal
First Posted: March 11, 2015    Key Record Dates
Last Update Posted: March 6, 2018
Last Verified: March 2018

Keywords provided by Joao F. Lacerda, Instituto de Medicina Molecular João Lobo Antunes:
Allogeneic hematopoietic stem cell transplantation
Graft vs host disease
Regulatory T cells

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases