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

Study Overview
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Brief Summary
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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

Detailed Description
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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: - negative depletion of CD8 and CD19 cells - positive selection of CD25 cells

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

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Stable immunosuppressive medication in the 4 weeks prior to initiation of treatment PS 0-2 ECOG Adequate liver, kidney, lung and hematopoietic system functions Exclusion Criteria: Pediatric patients Pregnant women Ongoing prednisone requirement >1 mg/kg/day (or equivalent) Concurrent use of calcineurin-inhibitor plus sirolimus (either agent alone is acceptable) New immunosuppressive medication in the 4 weeks prior Extra-corporeal Photopheresis or rituximab therapy in the 4 weeks prior Exposure to T-cell or IL-2 targeted medication (e.g. ATG, alemtuzumab, basiliximab, denileukin diftitox) within 100 days prior Donor lymphocyte infusion within 100 days prior Active malignant relapse Active uncontrolled infection HIV-infected patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of 0.5 x 10ˆ6 donor Treg/kg<br>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<br>* Regulatory T cells selected by a sequential 2 step procedure: - Negative selection of CD8 and CD19 cells - Positive selection of CD25 cells<br>|
| Experimental: Administration of 1.0 x 10ˆ6 donor Treg/kg<br>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<br>* Regulatory T cells selected by a sequential 2 step procedure: - Negative selection of CD8 and CD19 cells - Positive selection of CD25 cells<br>|
| Experimental: Administration of 2.0-3.0 x 10ˆ6 donor Treg/kg<br>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<br>* Regulatory T cells selected by a sequential 2 step procedure: - Negative selection of CD8 and CD19 cells - Positive selection of CD25 cells<br>|
| Experimental: Administration of MTD of donor T reg<br>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<br>* Regulatory T cells selected by a sequential 2 step procedure: - Negative selection of CD8 and CD19 cells - Positive selection of CD25 cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Progression of graft versus host disease and myelosuppression are indicators of toxicity and MTD associated with the infusion of donor regulatory T cells | Response evaluated 12 weeks after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic graft versus host disease improvement according to the 2014 NIH consensus criteria following the infusion of donor regulatory T cells |  | 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 |  | 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 |  | Response evaluated 12 months after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic hematopoietic stem cell transplantation, Graft vs host disease, Regulatory T cells