Trial Outcomes & Findings for Ultra-Low Dose Interleukin-2 for Refractory Chronic Graft Versus Host Disease (NCT NCT00529035)

NCT ID: NCT00529035

Last Updated: 2020-07-01

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 29 participants
• Primary outcome timeframe: Participants were assessed for toxicities at mandatory study follow-up visits during the 8 week course of study therapy and four weeks post therapy
• Results posted on: 2020-07-01

Participant Flow

Participant milestones

Measure	Ultra-low Dose Interleukin-2 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
Overall Study STARTED	29
Overall Study COMPLETED	28
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	Ultra-low Dose Interleukin-2 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
Overall Study Withdrawal by Subject	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Group 1 n=29 Participants 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)
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	29 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	46.5 years STANDARD_DEVIATION 12.7 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants
Region of Enrollment United States	29 participants n=5 Participants

PRIMARY outcome

Timeframe: Participants were assessed for toxicities at mandatory study follow-up visits during the 8 week course of study therapy and four weeks post therapy

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

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.

Outcome measures

Measure	Ultra-low Dose IL-2 MTD n=28 Participants	Median Absolute Cell Counts at Week 8 Immune-cell counts after 8 weeks of IL-2 therapy	Median Absolute Cell Count at Week 12 Immune-cell counts after a 4 weeks off IL-2 per protocol
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.	1 million IU/m2/day	—	—

SECONDARY outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Measure	Ultra-low Dose IL-2 MTD n=28 Participants	Median Absolute Cell Counts at Week 8 Immune-cell counts after 8 weeks of IL-2 therapy	Median Absolute Cell Count at Week 12 Immune-cell counts after a 4 weeks off IL-2 per protocol
The Number of Participants Who Tolerated at Least 6 Weeks of Subcutaneous Low Dose IL-2. Feasibility	23 participants	—	—
The Number of Participants Who Tolerated at Least 6 Weeks of Subcutaneous Low Dose IL-2. Efficacy	12 participants	—	—

SECONDARY outcome

Timeframe: Immunological samples taken at study appointments during the 12 week protocol schedule

Population: 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.

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).

Outcome measures

Measure	Ultra-low Dose IL-2 MTD n=22 Participants	Median Absolute Cell Counts at Week 8 n=19 Participants Immune-cell counts after 8 weeks of IL-2 therapy	Median Absolute Cell Count at Week 12 n=15 Participants Immune-cell counts after a 4 weeks off IL-2 per protocol
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. Tcon cell count	206 cells/cubic millimeter Interval 131.0 to 412.0	270 cells/cubic millimeter Interval 110.0 to 678.0	209 cells/cubic millimeter Interval 153.0 to 550.0
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. Treg cell count	17 cells/cubic millimeter Interval 6.0 to 35.0	101 cells/cubic millimeter Interval 43.0 to 236.0	32 cells/cubic millimeter Interval 11.0 to 92.0
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. CD8+ T cell count	210 cells/cubic millimeter Interval 113.0 to 419.0	202 cells/cubic millimeter Interval 74.0 to 418.0	187 cells/cubic millimeter Interval 55.0 to 502.0
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. Natural Killer (NK) cell count	158 cells/cubic millimeter Interval 94.0 to 250.0	362 cells/cubic millimeter Interval 170.0 to 570.0	203 cells/cubic millimeter Interval 132.0 to 311.0
CD3+T, CD4+T (Including Regulatory CD4+T Cells (Treg) and Conventional CD4+T Cells (Tcon)), CD8+T, NK, NKT and B Cell Counts. NKT cell count	28 cells/cubic millimeter Interval 10.0 to 46.0	31 cells/cubic millimeter Interval 18.0 to 53.0	22 cells/cubic millimeter Interval 10.0 to 38.0

SECONDARY outcome

Timeframe: Immunological samples taken at study appointments during the 12 week protocol schedule

Population: 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.

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).

Outcome measures

Measure	Ultra-low Dose IL-2 MTD n=22 Participants	Median Absolute Cell Counts at Week 8 n=19 Participants Immune-cell counts after 8 weeks of IL-2 therapy	Median Absolute Cell Count at Week 12 n=15 Participants Immune-cell counts after a 4 weeks off IL-2 per protocol
Treg Cell:Tcon Cell Ratio	0.07 ratio Interval 0.05 to 0.12	0.4 ratio Interval 0.24 to 0.71	0.14 ratio Interval 0.09 to 0.22

Adverse Events

Ultra-low Dose Interleukin-2

Serious events: 9 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ultra-low Dose Interleukin-2 n=29 participants at risk 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)
Blood and lymphatic system disorders Thrombotic microangiopathy with renal failure	6.9% 2/29 • Number of events 2 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Infections and infestations MRSA Pneumonia	3.4% 1/29 • Number of events 1 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Infections and infestations MRSA furuncle	3.4% 1/29 • Number of events 1 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Infections and infestations Hemophilius influenza type B bacteremia	3.4% 1/29 • Number of events 1 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Cardiac disorders Acute myocardial infarction	6.9% 2/29 • Number of events 2 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
General disorders Injection site induration	6.9% 2/29 • Number of events 2 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.

Other adverse events

Measure	Ultra-low Dose Interleukin-2 n=29 participants at risk 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)
General disorders Constitutional symptoms	6.9% 2/29 • Number of events 2 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Renal and urinary disorders Renal dysfunction (mild)	3.4% 1/29 • Number of events 1 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.
Blood and lymphatic system disorders Thrombocytopenia (mild)	3.4% 1/29 • Number of events 1 • 12 weeks. For patients who continued on extended-duration therapy, adverse events were reported as long as they received treatment.

Additional Information

John Koreth, MBBS, D.Phil

Dana-Farber Cancer Institute

Phone: (617) 632-2949

Email: jkoreth@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place