Donor Regulatory T-cells for cGVHD in Patients Who do Not Obtain Complete Remission With Ruxolitinib

Study Overview
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Brief Summary
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Phase II clinical trial to assess the efficacy of donor regulatory enriched T cells in steroid-refractory chronic graft versus host disease patients who did not obtain complete remission under treatment with ruxolitinib

Detailed Description
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A number of 15 patients will be included to assess the efficacy of donor regulatory enriched T cells in steroid-refractory chronic graft versus host disease patients who did not obtain complete remission after 12 weeks of treatment with ruxolitinib. The doses of Treg-enriched cells will be 2x10^6 cells/kg. Survival at 1 year after Treg infusion will be represented based on the clinical data with Kaplan Meier curves.

Official Title
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Phase II Trial of Donor Regulatory T-cells for Steroid-Refractory Chronic Graft-versus-Host-Disease in Patients Who do Not Obtain Complete Remission With Ruxolitinib

Conditions
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Chronic Graft vs Host Disease

Intervention / Treatment
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* Biological: Regulatory T-cell enriched infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of allogeneic hematopoietic stem cell transplantation Participants must have steroid-refractory cGVHD and had obtained any response other than progression after at least 12 weeks of treatment with ruxolitinib. Steroid-refractory cGVHD is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate glucocorticoids) without complete resolution of signs and symptoms. Stable dose of glucocorticoids for 4 weeks prior to enrollment. No addition or subtraction of other immunosuppressive medications (e.g., calcineurin-inhibitors, sirolimus, mycophenolate-mofetil) for 4 weeks prior to enrollment. The dose of immunosuppressive medicines may be adjusted based on the therapeutic range of that drug. No age limit. In the case of children participating in the study, the informed consent will be signed by a parents or legal guardians. Eastern Cooperative Oncology Group scale performance status 0-2 Participants must have adequate organ function Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Ongoing prednisone requirement >1 mg/kg/day (or equivalent). Concurrent use of calcineurin-inhibitor plus sirolimus (either agent alone is acceptable). History of active thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura in the last 6 months. New immunosuppressive medication in the 4 weeks prior to enrollment. Extra-corporeal Photopheresis or rituximab therapy in the 4 weeks prior to enrollment. Post-transplant exposure to T-cell or interleukin-2 targeted medication within 100 days prior to enrollment. Donor lymphocyte infusion within 100 days prior to enrollment. Active malignant relapse. Active uncontrolled infection. Organ transplant (allograft) recipient. HIV-positive individuals on combination antiretroviral therapy are ineligible. Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after hematopoietic stem cell transplant. Other investigational drugs within 4 weeks prior to enrollment, unless cleared by the Principal Investigator. Pregnant women are excluded from this study.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The doses of Treg-enriched cells will be 2x10^6 cells/kg
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regulatory T-cell enriched infusion<br>The doses of Regulatory T-cell enriched infusion will be 2x10^6 cells/kg | Biological: Regulatory T-cell enriched infusion<br>* Enrichment of CD25hi regulatory T cells from cluster of differentiation antigen 8 and/or cluster of differentiation antigen19 pre-depleted leukapheresis products.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with overall response rate. | Obtain ≥65% the overall response rate at 6 months after infusion | 6 months post-infusion | 
| Number of Participants with overall response rate. | Obtain ≥75% the overall response rate at 1 year after infusion | 1 year post-infusion | 
| Survival | Number of patients who survive after Regulatory T-cell enriched infusion | 1 year after Regulatory T-cell enriched infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease evaluation through Symptoms of the disease | Symptoms of the disease through chronic GVHD activity assessment (clinician) according to NIH consensus- form A | Screening, weeks 1, 2, 4, 6, 12 and months 6, 9 and 12 months after infusion | 
| Disease evaluation through measurement of quality of life | Measurement of quality of life through Functional Assessment of Cancer Therapy - Bone Marrow Transplantation | Screening, weeks 1, 2, 4, 6, 12 and months 6, 9 and 12 months after infusion | 
| Disease evaluation through Symptoms of the disease | Symptoms of the disease through chronic GVHD symptom scoring scale | Screening, weeks 1, 2, 4, 6, 12 and months 6, 9 and 12 months after infusion | 
| Immunosuppressive requirements. | Evaluation of needs of additional permitted immunosuppressive treatment administered as concomitant medication | Screening, month1, months 3, 6, and 12 after infusion | 
| Free survival | To evaluate failure free survival (change of immunosuppression, mortality or relapse) | 1 year after infusion. | 
| Immunologic monitoring and in vivo Treg tracking through inmune globulings | Quantitative immune globulins | 1 year after infusion and after infusion | 
| Immunologic monitoring and in vivo Treg tracking through plasma | Plasma banking | 1 year after infusion and after infusion | 
| Immunologic monitoring and in vivo Treg tracking through mononuclear cells | Storage of additional mononuclear cells | 1 year after infusion and after infusion | 
| Immunologic monitoring and in vivo Treg tracking through lymphocyte | Detailed immunological evaluation of lymphocyte | 1 year after infusion and after infusion | 
| Immunologic monitoring and in vivo Treg tracking through Natural Killer cell subsets | Quantitative Natural Killer cell subsets | 1 year after infusion and after infusion | 
| Purity of Treg-enriched cell infusion | Percentage of cells viability, negative gram stain/endotoxin, percentage of CD4+CD25+ cells and CD4+CD25+CD127- Treg in order to consider for the infusion. | Before 24 hours to infusion up infusion day | 
| Toxicity monitoring of Treg-enriched cells | Number of grade 3 or higher Adverse Events and all Serious Adverse Events according to the Version 5.0 of the NCI Common Terminology Criteria for Adverse Events. | Weeks 1, 2, 4, 6, 12 and months 6, 9 and 12 after infusion | 
| Life-threatening infections | Number of infections | Weeks 1, 2, 4, 6, 12 and months 6, 9 and 12 after infusion | 
| Predictors of clinical response | Quantify predictors of clinical response among patients receiving ruxolitinib | 1 year after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ruxolitinib, T cells