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

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00529035
• Collaborator: Brigham and Women's Hospital (Other), Novartis (Industry)
• Enrollment: 29
• Location: 1
• Arm: 1
• Duration (Months): 153.9
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: Interleukin-2	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: May 27, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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)	Drug: Interleukin-2; Dose will vary depending upon when participant enters the trial: Given as a daily injection under the skin for 8 weeks.; Other Names: IL-2

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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).

3. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Novartis

Investigators

• Principal Investigator: John Koreth, MBBS, D.Phil, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00529035
• Other Study ID Numbers: 07-083
• First Posted: Sep 14, 2007
• Last Update Posted: Jul 1, 2020
• Last Verified: Jun 1, 2020

• Keywords provided by John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute: Chronic GVHD; Steroid refractory GVHD; allogeneic stem cell transplantation
• Additional relevant MeSH terms: Graft vs Host Disease; Interleukin-2

Study Results

Participant Flow

Arm/Group Title	Ultra-low Dose Interleukin-2
Arm/Group Description	Daily subcutaneous administration of Interleukin-2 evaluated at three dose levels: 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
Period Title: Overall Study
STARTED	29
COMPLETED	28
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Group 1
Arm/Group 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)
Overall Participants	29
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.5 (12.7)
Sex: Female, Male (Count of Participants)
Female	8 27.6%
Male	21 72.4%
Region of Enrollment (participants) [Number]
United States	29 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

One participant terminated therapy early and was not evaluable for this outcome measure.

Arm/Group Title	Ultra-low Dose IL-2 MTD
Arm/Group Description
Measure Participants	28
Number [million IU/m2/day]	1

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were evaluable for response and considered meeting the feasibility endpoint if they completed at least 6 weeks of treatment. Participants who had a partial response or complete response in cGVHD to treatment were considered to meet the efficacy endpoint.

Arm/Group Title	Ultra-low Dose Interleukin-2
Arm/Group Description
Measure Participants	28
Feasibility	23 79.3%
Efficacy	12 41.4%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were evaluated for regulatory T cell (Treg) expansion and other immune-cell changes while on low-dose IL-2 therapy. Participants had blood samples drawn at study appointments during the 12 week protocol schedule. Please note that for NK and NKT cell counts, only 18 participants samples were analyzed.

Arm/Group Title	Median Absolute Cell Counts at Baseline	Median Absolute Cell Counts at Week 8	Median Absolute Cell Count at Week 12
Arm/Group Description	Immune-cell counts before the start of IL-2 therapy	Immune-cell counts after 8 weeks of IL-2 therapy	Immune-cell counts after a 4 weeks off IL-2 per protocol
Measure Participants	22	19	15
Treg cell count	17	101	32
Tcon cell count	206	270	209
CD8+ T cell count	210	202	187
Natural Killer (NK) cell count	158	362	203
NKT cell count	28	31	22

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were evaluated for changes to the ratio of regulatory T cell (Treg) and conventional T cell (Tcon) counts while on IL-2 therapy. Participants had blood samples drawn at study appointments during the 12 week protocol schedule to analyze the immunological effects of low-dose IL-2 therapy.

Arm/Group Title	Median Treg:Tcon Ratio at Baseline	Median Treg:Tcon Ratio at Week 8	Median Treg:Tcon Ratio at Week 12
Arm/Group Description	Immune-cell ratio before the start of IL-2 therapy	Immune-cell ratio after 8 weeks of IL-2 therapy	Immune-cell ratio after a 4 weeks off IL-2 per protocol
Measure Participants	22	19	15
Median (Inter-Quartile Range) [ratio]	0.07	0.4	0.14

Adverse Events

Time Frame	12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Arm/Group Title	Ultra-low Dose Interleukin-2
Arm/Group 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)
All Cause Mortality
	Ultra-low Dose Interleukin-2
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ultra-low Dose Interleukin-2
	Affected / at Risk (%)	# Events
Total	9/29 (31%)
Blood and lymphatic system disorders
Thrombotic microangiopathy with renal failure	2/29 (6.9%)	2
Cardiac disorders
Acute myocardial infarction	2/29 (6.9%)	2
General disorders
Injection site induration	2/29 (6.9%)	2
Infections and infestations
MRSA Pneumonia	1/29 (3.4%)	1
MRSA furuncle	1/29 (3.4%)	1
Hemophilius influenza type B bacteremia	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Ultra-low Dose Interleukin-2
	Affected / at Risk (%)	# Events
Total	4/29 (13.8%)
Blood and lymphatic system disorders
Thrombocytopenia (mild)	1/29 (3.4%)	1
General disorders
Constitutional symptoms	2/29 (6.9%)	2
Renal and urinary disorders
Renal dysfunction (mild)	1/29 (3.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.