Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of donor regulatory T cells in treating patients with graft-versus-host disease affecting the liver or gastrointestinal organs (visceral) within 100 days (acute) after undergoing a stem cell transplant. Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a type of immune cell that may be able to reduce the attack of the donor's immune cells on the patient's normal cells and help treat graft-vs-host disease.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and feasibility of donor T regulatory (Treg) cell infusions in subjects with visceral acute graft-versus-host disease (aGVHD) and incidence of dose limiting toxicities (DLTs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE version 4 [v.4]) with a focus on infusion reactions within 24 hours, respiratory distress within 72 hours of infusion and all-cause mortality within 28 days of infusion. SECONDARY OBJECTIVES: I. Determine the quantitative blood Treg cell changes following the cell infusions. II. Assess dosing requirements and treatment response rates to primary steroid, secondary and tertiary immunosuppressive therapy. III. Post-transplant day +100 and day +180 survival. IV. Post-transplant incidence of chronic graft-versus-host disease (GVHD) at day +180. OUTLINE: This is a dose-escalation study. Patients receive donor regulatory T lymphocytes intravenously (IV) over 5 minutes or less on day 0. Some patients receive a second infusion of frozen donor regulatory T lymphocytes 5-7 days after the initial infusion or 2 additional infusions separated by 5-7 days. After completion of study treatment, patients are followed up weekly until day 28 and then on days 100 and 180.

Official Title
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A Phase 1 Single Center Safety and Feasibility Study of Primary T Regulatory Cell Therapy to Treat Visceral Acute Graft-versus-Host Disease Following Hematopoietic Cell Transplantation

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Biological: donor regulatory T lymphocytes
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Visceral aGVHD defined as: at least stage III/IV acute liver or stage II/III gastrointestinal (GI) GVHD by clinical criteria and/or GI and/or liver biopsy confirmation showing no alternative explanation for symptoms of GVHD Ability to understand and willingness to sign a written informed consent form Must have a 7/8 or 8/8 or haploidentical related donor matched at the human leukocyte antigen (HLA)-A, B, C, DRB1 who was evaluated and provided the donor transplant graft Myeloablative or non-myeloablative allogeneic hematopoietic cell transplantation Karnofsky performance status >= 50 DONOR: Age >= 18 to =< 77 years old DONOR: Karnofsky performance status of >= 70% defined by institutional standards DONOR: Must be the same sibling donor from whom the recipient's blood and marrow graft was collected for the original allogeneic transplant that is HLA 7/8 or 8/8 or haploidentical matched at the HLA-A, B, C, and DRB1 DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-cell lymphotropic virus (HTLV) 1 and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR)+, or hepatitis C Ab or PCR+, syphilis (Treponema) screen and HIV 1 and hepatitis C by NAT (nucleic acid testing) have been collected prior to apheresis DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within two weeks of apheresis DONOR: Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate DONOR: Donor selection will be in compliance with 21 Code of Federal Regulations (CFR) 1271 Exclusion Criteria: Uncontrolled infections not responsive to antimicrobial therapy requiring intensive critical care Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy Cytomegalovirus colitis or enteritis as defined by cytomegalovirus (CMV) shell vial or culture positivity from endoscopic biopsy the discretion of the treating physician based upon PCR positivity, clinical presentation and histology Respiratory insufficiency with oxygen requirement > 4 L nasal cannula Multi-organ failure DONOR: Evidence of active infection or viral hepatitis DONOR: HIV positive DONOR: Pregnant donor DONOR: Factors which place the donor at increased risk for complications from leukapheresis

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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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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (donor regulatory T lymphocytes)<br>Patients receive donor regulatory T lymphocytes intravenously (IV) over 5 minutes or less on day 0. Some patients receive a second infusion of frozen donor regulatory T lymphocytes 5-7 days after the initial infusion or 2 additional infusions separated by 5-7 days. | Biological: donor regulatory T lymphocytes<br>* Given IV<br>* Other names: donor CD4+CD25+FoxP3+ T cells;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3 infusion reaction within 24 hours of infusion | Dose-limiting toxicity will be defined as CTCAE Grade 3 or higher cytokine/release syndrome/acute infusion reaction within 24 hours after Treg cell infusion. The rates of defined DLTs will be calculated and the one-sided upper 80%, 90%, and 95% confidence limits calculated. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade 3 or higher non-GVHD infusion-related adverse events | Incidence of grade 3 or higher non-GVHD infusion-related adverse events according to the CTCAE v4 that are not anticipated following HCT will be reported | Up to day 28 | 
| Grade 4 (life threatening) or 5 (fatal) adverse events | Grade 4 (life threatening) or 5 (fatal) adverse events within after 28 days of Treg infusion that were otherwise unexpected in the immediate post transplant setting will be reported | 28 days | 
| Grade 4 (life threatening) respiratory distress | Grade 4 (life threatening) respiratory distress within 72 hours of Treg infusion will be reported | 72 hours | 
| Change in blood Treg cell numbers following the infusions | The change in Treg cell counts from baseline to post infusion will be depicted in boxplots of both relative proportion and absolute numbers. Mean log (fold change) and confidence intervals will be calculated. The confidence intervals will be used to test the hypotheses of no change from baseline to post infusion. | Baseline to up to day 28 | 
| Overall survival (OS) | The OS will be estimated by the Kaplan-Meier product-limit method, with standard confidence limits. | Day 100 | 
| Incidence of cGVHD. | Incidence of cGVHD will be reported at Post HCT day +180 | 180 days |