In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis

Study Overview
=================
Brief Summary
-----------------
IL-2 add-back post allogeneic hematopoietic stem cell transplant (HSCT), combined with Sirolimus (SIR), Tacrolimus (TAC) will optimize Treg reconstitution and prevent graft versus host disease (GVHD).

Detailed Description
-----------------
1) Determine if a GVHD prophylaxis regimen of IL-2/SIR/TAC enhances in vivo Treg differentiation and growth; 2) Study the safety and effects of IL-2/SIR/TAC on the incidence of acute and chronic GVHD; 3) Evaluate the influence of dual IL-2 supplementation and mammalian target of rapamycin (mTOR) inhibition on T cell-specific signaling pathways and the polarization of emerging T helper cells.

Official Title
-----------------
In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis With IL-2, Sirolimus, and Tacrolimus Following Allogeneic Hematopoietic Cell Transplantation

Conditions
-----------------
Graft-Versus-Host-Disease

Intervention / Treatment
-----------------
* Drug: IL-2
* Drug: Tacrolimus
* Drug: Sirolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have an available 8/8 human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 matched-related or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft. Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myeloproliferative neoplasms requiring a matched allogeneic HSCT. Acute Leukemia (AML or ALL) must be in complete remission defined as: <5% marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, marrow >20% cellular, and peripheral absolute neutrophil count >1000/µL (platelet recovery is not required). Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have <5% marrow blasts. Myeloproliferative neoplasms (MPN): Must have <5% peripheral / marrow blasts. Adequate vital organ function: Left ventricular ejection fraction (LVEF) ≥ 45% by multi gated acquisition (MUGA) scan or ECHO Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing lung capacity oxygenation (DLCO) ≥ 50% of predicted values on pulmonary function tests Transaminases (AST, ALT) < 2 times upper limit of normal values Creatinine clearance ≥ 50 cc/min. Performance status: Karnofsky Performance Status Score ≥ 80% Donor eligibility: Eligible donors will include healthy sibling, relative or unrelated donors that are matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing. Exclusion Criteria: Active infection not controlled with appropriate antimicrobial therapy History of HIV, hepatitis B, or hepatitis C infection Anti-thymocyte globulin, alemtuzumab, bortezomib, or cyclophosphamide administered within 14 days before or planned to receive with HCT conditioning or as part of GVHD prophylaxis in the 14 days after HCT. Hypersensitivity to recombinant human IL-2 Chronic lymphocytic leukemia, Hodgkin lymphoma, and non-hodgkin lymphoma are excluded as these malignancies may express the IL-2 receptor and pose a potential growth signal to any present disease. Sorror's co-morbidity factors with total score >4

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GVHD Regimen<br>Graft versus host disease (GVHD) prophylaxis regimen IL-2 with Sirolimus and Tacrolimus after allogeneic hematopoietic cell transplant (HCT). | Drug: IL-2<br>* A subcutaneous injection will be administered 3 times a week (separated by at least 1 day between injections), from day 0 to +90 (+/- 7 days).<br>* Other names: (aldesleukin);Drug: Tacrolimus<br>* Will be administered at 0.01 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3<br>Drug: Sirolimus<br>* Orally on day -1. The dose for loading is 12 mg by mouth (PO)<br>* Other names: Rapamune;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT | Percentage of Treg among blood CD4+ T cells at day 30 after hematopoietic cell transplantation (HCT), to compare to SIR/TAC alone data from a previous trial (median of 16%). The study was designed to capture an increase in regulatory T cells from a median of 16.0% at day +30. | 30 days post HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at Day +365 | Overall survival will be defined as the time from transplant date to death from any cause. | 365 days post HCT | 
| Cumulative Incidence of Relapse | Incidence of primary disease relapse per standard definitions. | 1 year post HCT | 
| Cumulative Incidence of Grade II-IV Acute GVHD by Day +100 | Acute GVHD will be graded per the 1995 consensus guidelines. | 100 days post HCT | 
| Cumulative Incidence of Chronic GVHD by Day +365 | Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria. | 365 days post HCT | 
| Incidence of Non-relapse Death | Incidence of Non-relapse death/Transplant-related mortality. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation. | 365 days post HCT | 
| Incidence of Unexpected or Serious Adverse Events (AEs) | Grade 3-5 unexpected or serious adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.03) were captured up to day +130 or 30 days after the last dose of IL-2. Events listed, with causality in relation to study treatment noted. | Up to days 130 post HCT | 
| Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT | The proportion of Tregs to non-Treg CD4+ cells to be assessed at day +90. Natural Killer Cells (NKs): Median K/uL NK cells. | 90 days post HCT | 
| STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30 | Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +30. | 30 days post HCT | 
| STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90 | Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +90. | 90 days post HCT | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GVHD, Allogeneic, Hematopoietic Cell Transplant