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

Overview

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2019

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

Interventions

  • Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease
    • Regulatory T cells selected by a sequential 2 step procedure: - Negative selection of CD8 and CD19 cells - Positive selection of CD25 cells

Arms, Groups and Cohorts

  • 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.
  • 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.
  • 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.
  • 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

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • 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
  • 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
  • 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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Instituto de Medicina Molecular João Lobo Antunes
  • Collaborator
    • Hospital de Santa Maria, Portugal
  • Provider of Information About this Clinical Study
    • Principal Investigator: Joao F. Lacerda, MD PhD, Associate Professor of Medicine – Instituto de Medicina Molecular João Lobo Antunes

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