Ultra-Low Dose Interleukin-2 for Refractory Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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The purpose of this research study is to determine the safety of IL-2 and the highest dose of this drug that can be given safely to people with chronic graft versus host disease (GVHD). Chronic GVHD is a medical condition that may occur after patients receive a bone marrow, stem cell or cord blood transplant. The donor's immune system may recognize their body (the host) as foreign and attempt to reject it. Traditional standard therapy to treat chronic GVHD is prednisone (steroids). Treatment options are limited, and it is thought that IL-2 may help to control chronic GVHD.

Detailed Description
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IL-2 will be given daily through an injection under the skin for a period of 8 weeks. To determine the highest safest dose of IL-2, the dose participants receive will increase as lower doses are determined to be safe. There will be three dose levels. Participants will be seen periodically while they are receiving IL-2. Physical exams and blood tests will be performed weekly for the first two weeks and then every other week until week 8.

Official Title
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A Phase I Study of Ultra-Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease

Conditions
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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: Recipients of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens Patients must be at least 180 days from the allogeneic stem cell transplantation procedure Steroid refractory cGVHD, defined as having persistent symptoms and signs of GVHD despite the use of prednisone for at least 4 weeks in the preceding 12 months without complete resolution of signs and symptoms. Stable dose of corticosteroids for 4 weeks prior to enrollment No addition or subtraction of other immunosuppressive medications for 4 weeks prior to enrollment. Adequate bone marrow, renal and hepatic function as outlined in the protocol 18 years of age or older ECOG Performance Status of 0-2 Exclusion Criteria: Ongoing prednisone requirement > 1mg/kg/day (or equivalent) Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment Concurrent ECP therapy within 4 weeks prior to enrollment Post-transplant exposure to any novel immunosuppressive medication within 100 days prior to enrollment Donor lymphocyte infusion within 100 days prior to IL-2 therapy Active malignant disease relapse Active, uncontrolled infection Positive serologic test for Hepatitis B or a positive serologic or nucleic acid test for Hepatitis C HIV seropositivity Life expectancy < 3 months Pregnancy or lactation Inability to comply with IL-2 treatment regimen Uncontrolled cardiac angina or symptomatic congestive heart failure Organ transplant (allograft) recipient

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>Interleukin-2 (IL-2) will be given daily through an injection under the skin for a period of 8 weeks. To determine the highest safest dose of IL-2, the dose participants receive will increase as lower doses are determined to be safe. There will be three dose levels: Dose Level -A 0.3 x 106 (IU/m2/d) Dose Level -B 1 x 106 (IU/m2/d) Dose Level-C 3 x 106 (IU/m2/d) | Drug: Interleukin-2<br>* Dose will vary depending upon when participant enters the trial: Given as a daily injection under the skin for 8 weeks.<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose and Toxicity Profile of an 8 Week Course of IL-2 in Patients With cGVHD and an Inadequate Response to Steroids. | Three dose levels were evaluated to determine the maximally tolerated dose (MTD): Dose level A: 0.3 x 10^6 IU/m^2/day Dose level B: 1.0 x 10^6 IU/m^2/day Dose level C: 3.0 x 10^6 IU/m^2/day Once the MTD (dose level B) was established, an additional 10 participants were enrolled at this dose. | Participants were assessed for toxicities at mandatory study follow-up visits during the 8 week course of study therapy and four weeks post therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Who Tolerated at Least 6 Weeks of Subcutaneous Low Dose IL-2. | Feasibility: the number of participants who tolerated at least 6 weeks of therapy, and were thus evaluable for response. Efficacy: chronic GVHD response per NIH consensus criteria in evaluable patients. A complete response was defined as resolution of all reversible chronic GVHD-associated manifestations, a partial response as an improvement of 50% or more on the organ-specific chronic GVHD scale without progression at other organs or sites, progressive disease as an increase of 25% or more on the organ specific chronic GVHD scale, and stable disease as an improvement of less than 50% or increase of less than 25%. Please refer to the Supplementary Appendix in our published report (Koreth et al, NEJM 2011) for further details. | Participants were assessed for toxicities at mandatory study follow-up visits during the 8 week course of study therapy and four weeks post therapy. cGVHD was assessed at Weeks 8 and 12 | 
| CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. | Changes in the above immune cell populations (CD3+T, CD4+T (including CD4+Treg and CD4+Tcon), CD8+T, NK, NKT and B cell counts were measured at study appointments during the 8-week IL-2 treatment and four weeks post study therapy. All study participants (n=28) with a sample available were reported in the data table. Immune outcome data cannot be meaningfully rendered in the template provided, owing to complexity. The tables below only represent a general overview of the data. Please refer to figure 2 in our published report (Koreth et al, NEJM 2011). | Immunological samples taken at study appointments during the 12 week protocol schedule | 
| Treg Cell:Tcon Cell Ratio | Changes in the ratio of the CD4+ regulatory T cell (Treg) and CD4+ conventional T cell (Tcon) counts were measured at study appointments during the 8-week IL-2 treatment and four weeks post study therapy. All study participants (n=28) with a sample available were reported in the data table. Immune outcome data cannot be meaningfully rendered in the template provided, owing to complexity. The tables below only represent a general overview of the data. Please refer to figure 2 in our published report (Koreth et al, NEJM 2011). | Immunological samples taken at study appointments during the 12 week protocol schedule | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic GVHD, Steroid refractory GVHD, allogeneic stem cell transplantation