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

Primary Purpose

Graft Versus Host Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Interleukin-2
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring Chronic GVHD, Steroid refractory GVHD, allogeneic stem cell transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Dana-Farber Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Interleukin-2

Arm Description

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)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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).
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).

Full Information

First Posted
September 11, 2007
Last Updated
June 22, 2020
Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT00529035
Brief Title
Ultra-Low Dose Interleukin-2 for Refractory Chronic Graft Versus Host Disease
Official Title
A Phase I Study of Ultra-Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
June 2011 (Actual)
Study Completion Date
May 27, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Brigham and Women's Hospital, Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease
Keywords
Chronic GVHD, Steroid refractory GVHD, allogeneic stem cell transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Interleukin-2
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Interleukin-2
Other Intervention Name(s)
IL-2
Intervention Description
Dose will vary depending upon when participant enters the trial: Given as a daily injection under the skin for 8 weeks.
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
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 Measure Information:
Title
The Number of Participants Who Tolerated at Least 6 Weeks of Subcutaneous Low Dose IL-2.
Description
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.
Time Frame
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
Title
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts.
Description
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).
Time Frame
Immunological samples taken at study appointments during the 12 week protocol schedule
Title
Treg Cell:Tcon Cell Ratio
Description
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).
Time Frame
Immunological samples taken at study appointments during the 12 week protocol schedule

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Koreth, MBBS, D.Phil
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22129252
Citation
Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, Armand P, Cutler C, Ho VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011 Dec 1;365(22):2055-66. doi: 10.1056/NEJMoa1108188.
Results Reference
result

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

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