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

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 Overview

• Status: Unknown
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Biological: Donor regulatory T cell adoptive immunotherapy in chronic graft versus host disease

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
• Enrollment (Anticipated): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / 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: - Negative selection of CD8 and CD19 cells; - 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: - Negative selection of CD8 and CD19 cells; - 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: - Negative selection of CD8 and CD19 cells; - 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: - Negative selection of CD8 and CD19 cells; - Positive selection of CD25 cells

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Instituto de Medicina Molecular João Lobo Antunes
• Collaborators: Hospital de Santa Maria, Portugal; IPOFG Lisboa, Portugal; IPOFG Porto, Portugal

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Anticipated): March 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: March 1, 2015
• First Submitted That Met QC Criteria: March 10, 2015
• First Posted (Estimate): March 11, 2015

Study Record Updates

• Last Update Posted (Actual): March 6, 2018
• Last Update Submitted That Met QC Criteria: March 4, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Regulatory T cells; Allogeneic hematopoietic stem cell transplantation; Graft vs host disease
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: TREGeneration-Portugal