Daily IL-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease

Study Overview
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Brief Summary
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Chronic GVHD is a medical condition that may occur after a bone marrow, stem cell or cord blood transplant. The donor's immune system may recognize the your body (the host) as foreign and attempt to 'reject' it. This process is known as graft-versus-host-disease. It is thought that IL-2 may help control chronic GVHD by stopping the donor's immune system from 'rejecting' your body. In this research study, we are looking to see how IL-2 can be used in combination with steroids to treat cGVHD.

Detailed Description
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You will give yourself or be given IL-2 daily through an injection under your skin. You should rotate the injection site, if possible. You will do this once every day for 12 weeks. You will then have 4 weeks off of IL-2. During the first 6 weeks of IL-2, you will continue to take steroids without changing the dose your doctor has set for you while you are on IL-2. After 6 weeks of IL-2 therapy, your doctor may reduce the amount of steroids you take. While you are on study, a member of the study team will examine you to evaluate your cGVHD. These assessments may include examination of your skin, joints/muscles, eyes, mouth, lungs and gastrointestinal system. You will have clinic visits for evaluation of toxicity and clinical benefit approximately every 4 weeks. You will also have immunologic assays approximately every 8 weeks. Immunologic assays will measure the effect of IL-2 on immune cells. You will be on the study for about 16 weeks. You may continue on study treatment for longer if you experience a clinical benefit.

Official Title
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A Phase II Trial of Daily Low-Dose Interleukin-2 (IL-2) for Steroid-Refractory Chronic Graft-Versus-Host-Disease

Conditions
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Chronic Graft-versus-host Disease

Intervention / Treatment
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* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens Steroid refractory cGVHD with systemic therapy onset within the prior 6 months No more than 2 prior lines of cGVHD therapy Estimated life expectancy > 3 months Adequate organ function Exclusion Criteria: Ongoing prednisone requirement > 1 mg/kg/day (or equivalent) Concurrent use of calcineurin-inhibitors plus sirolimus History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura Active malignant relapse Active uncontrolled infection Uncontrolled cardiac angina or symptomatic congestive heart failure Organ transplant (allograft) recipient HIV-positive on combination antiretroviral therapy Active hepatitis B or C Pregnant or breast-feeding

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: Interleukin-2<br>Each study participant will receive daily subcutaneous IL-2 (1 x 106 IU/m2/day) for self-administration for 12 weeks, followed by a 4-week hiatus. IL-2 will be typically administered on an outpatient basis. After completing the 16 week study (12 weeks of IL-2 study treatment and a mandatory 4 weeks off-IL-2), patients experiencing clinical benefit (complete or partial response; as well as minor response not meeting NIH criteria for partial response) with an acceptable toxicity profile will be permitted to continue extended-duration treatment indefinitely at the discretion of the treating physician. | Drug: Interleukin-2<br>* Daily subcutaneous IL-2 (1 x 10^6 IU/m^2/day) for self-administration for 12 weeks followed by 4-week hiatus<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate of Low-dose Daily SC IL-2 in Steroid-refractory cGVHD | Participants were evaluated according to the cGVHD NIH Consensus criteria at baseline, 6 weeks, and 12 weeks on study. Per cGVHD NIH Consensus criteria, cGVHD involved organ systems are given a grade 0-3 and an overall cGVHD score, from 0-10, is given. Complete Response is defined as resolution of all reversible manifestations in each organ or site of cGVHD. A partial response is defined as an improvement in measure at least one organ or site, or decrease in global ratings by at least a 2-point change on the 10-point scale, without progression measured at any other organ or site. Non-responders have no change in cGVHD meeting criteria for either partial response or disease progression. Progressive disease is defined as an increase in organ or site scales (1-point change on a 3-point scale) or 2- to 3-point increase on the global cGVHD ratings. Clinical worsening of cGVHD is not synonymous with progressive cGVHD per NIH criteria. | Baseline, 6 weeks, and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of 12-week Course of Low-dose SC IL-2 Therapy | Participants were evaluated at clinical visits for toxicities related to IL-2 throughout their 12-week treatment course | 12 weeks | 
| Prednisone Taper With IL-2 Therapy | Participants had their steroid dose assessed at weeks 6, 12,16, and every 8 weeks while on extended duration IL-2 therapy. | End of treatment after 16 weeks or most recent follow-up date for patients on extended | 
| Overall Survival and Progression-free Survival | Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. OS was defined as from the study entry to death from any cause. Patients who were alive or lost to follow-up were censored at the time last seen alive. PFS was defined from the study entry to disease relapse or progression or death from any cause, whichever occurred first. | 2 years from start of IL-2 | 
| Immunologic Effects of Low-dose Daily SC IL-2: Treg Cell Counts | Blood samples were collected throughout the patient's 12 weeks of IL-2 treatment and after the 4 week hiatus. The CD4+CD25+FOXP3+ regulatory T cells (Treg) counts were measured. | 16 weeks of study follow-up | 
| Immunologic Effects of Low-dose Daily SC IL-2: Treg/Tcon Ratio | Blood samples were collected throughout the patient's 12 weeks of IL-2 treatment and after the 4 week hiatus. The ratio between CD4+CD25+FOXP3+ regulatory T cells (Treg) and CD4 conventional T cell (Tcon) counts were measured. | 16 weeks of study follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stem cell transplant, GVHD, bone marrow transplant, cord blood transplant, regulatory T cell, interleukin