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

Phase 1

Completed

Conditions: Graft Versus Host Disease

Interventions: Drug: Interleukin-2

Registration Number: NCT00529035

Lead Sponsor: Dana-Farber Cancer Institute

Brief Summary: 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: * 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 29

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Interleukin-2	Interleukin-2	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)

Primary Outcome Measures

Name	Time	Method
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.	Participants were assessed for toxicities at mandatory study follow-up visits during the 8 week course of study therapy and four weeks post therapy	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.

Secondary Outcome Measures

Name	Time	Method
The Number of Participants Who Tolerated at Least 6 Weeks of Subcutaneous Low Dose IL-2.	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	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.
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts.	Immunological samples taken at study appointments during the 12 week protocol schedule	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).
Treg Cell:Tcon Cell Ratio	Immunological samples taken at study appointments during the 12 week protocol schedule	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).