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

Phase 1

• Conditions: Graft vs Host Disease
• Interventions: Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

• Registration Number: NCT02385019
• Lead Sponsor: 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

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 Timeline

• Study Start: 2015-03
• Study First Submitted: 2015-03-01
• Study First Submitted QC: 2015-03-10
• Study First Posted: 2015-03-11
• Status Verified: 2018-03
• Last Update Submitted: 2018-03-04
• Last Update Posted: 2018-03-06
• Primary Completion: 2019-03
• Study Completion: 2019-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 22

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Administration of 2.0-3.0 x 10ˆ6 donor Treg/kg	Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease	Third group of 5 patients will receive a total of 2.0-3.0 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.
Administration of 1.0 x 10ˆ6 donor Treg/kg	Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease	Second group of 5 patients will receive a total of 1.0 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.
Administration of MTD of donor T reg	Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease	Preliminary Phase 2 study will include another 5 to 10 patients at the MTD identified in the Phase 1 study
Administration of 0.5 x 10ˆ6 donor Treg/kg	Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease	First group of 5 patients will receive a total of 0.5 x 10ˆ6 donor Treg/kg. Part of Phase 1 study.

Primary Outcome Measures

Name	Time	Method
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	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

Name	Time	Method
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

Trial Locations

Locations (2)

Instituto Portugues de Oncologia; 🇵🇹 Porto, Portugal

Hospital de Santa Maria, Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular; 🇵🇹 Lisboa, Portugal