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In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis

Primary Purpose

Graft-Versus-Host-Disease

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

IL-2

Tacrolimus

Sirolimus

About this trial

This is an interventional prevention trial for Graft-Versus-Host-Disease focused on measuring GVHD, Allogeneic, Hematopoietic Cell Transplant

Eligibility Criteria

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

Inclusion Criteria:

Patients must have an available 8/8 human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 matched-related or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft.
Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myeloproliferative neoplasms requiring a matched allogeneic HSCT.
- Acute Leukemia (AML or ALL) must be in complete remission defined as: <5% marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, marrow >20% cellular, and peripheral absolute neutrophil count >1000/µL (platelet recovery is not required).
- Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have <5% marrow blasts.
- Myeloproliferative neoplasms (MPN): Must have <5% peripheral / marrow blasts.
Adequate vital organ function:
1. Left ventricular ejection fraction (LVEF) ≥ 45% by multi gated acquisition (MUGA) scan or ECHO
2. Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing lung capacity oxygenation (DLCO) ≥ 50% of predicted values on pulmonary function tests
3. Transaminases (AST, ALT) < 2 times upper limit of normal values
4. Creatinine clearance ≥ 50 cc/min.
Performance status: Karnofsky Performance Status Score ≥ 80%
Donor eligibility: Eligible donors will include healthy sibling, relative or unrelated donors that are matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing.

Exclusion Criteria:

Active infection not controlled with appropriate antimicrobial therapy
History of HIV, hepatitis B, or hepatitis C infection
Anti-thymocyte globulin, alemtuzumab, bortezomib, or cyclophosphamide administered within 14 days before or planned to receive with HCT conditioning or as part of GVHD prophylaxis in the 14 days after HCT.
Hypersensitivity to recombinant human IL-2
Chronic lymphocytic leukemia, Hodgkin lymphoma, and non-hodgkin lymphoma are excluded as these malignancies may express the IL-2 receptor and pose a potential growth signal to any present disease.
Sorror's co-morbidity factors with total score >4

Sites / Locations

H. Lee Moffitt Cancer Center and Research Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

GVHD Regimen

Arm Description

Graft versus host disease (GVHD) prophylaxis regimen IL-2 with Sirolimus and Tacrolimus after allogeneic hematopoietic cell transplant (HCT).

Outcomes

Primary Outcome Measures

Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT

Percentage of Treg among blood CD4+ T cells at day 30 after hematopoietic cell transplantation (HCT), to compare to SIR/TAC alone data from a previous trial (median of 16%). The study was designed to capture an increase in regulatory T cells from a median of 16.0% at day +30.

Secondary Outcome Measures

Overall Survival at Day +365

Overall survival will be defined as the time from transplant date to death from any cause.

Cumulative Incidence of Relapse

Incidence of primary disease relapse per standard definitions.

Cumulative Incidence of Grade II-IV Acute GVHD by Day +100

Acute GVHD will be graded per the 1995 consensus guidelines.

Cumulative Incidence of Chronic GVHD by Day +365

Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria.

Incidence of Non-relapse Death

Incidence of Non-relapse death/Transplant-related mortality. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation.

Incidence of Unexpected or Serious Adverse Events (AEs)

Grade 3-5 unexpected or serious adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.03) were captured up to day +130 or 30 days after the last dose of IL-2. Events listed, with causality in relation to study treatment noted.

Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT

The proportion of Tregs to non-Treg CD4+ cells to be assessed at day +90. Natural Killer Cells (NKs): Median K/uL NK cells.

STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30

Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +30.

STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90

Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +90.

Full Information

NCT ID

NCT01927120

First Posted

August 16, 2013

Last Updated

June 1, 2017

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT01927120

Brief Title

In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis

Official Title

In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis With IL-2, Sirolimus, and Tacrolimus Following Allogeneic Hematopoietic Cell Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

March 25, 2014 (Actual)

Primary Completion Date

August 25, 2016 (Actual)

Study Completion Date

March 9, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

H. Lee Moffitt Cancer Center and Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

IL-2 add-back post allogeneic hematopoietic stem cell transplant (HSCT), combined with Sirolimus (SIR), Tacrolimus (TAC) will optimize Treg reconstitution and prevent graft versus host disease (GVHD).

Detailed Description

1) Determine if a GVHD prophylaxis regimen of IL-2/SIR/TAC enhances in vivo Treg differentiation and growth; 2) Study the safety and effects of IL-2/SIR/TAC on the incidence of acute and chronic GVHD; 3) Evaluate the influence of dual IL-2 supplementation and mammalian target of rapamycin (mTOR) inhibition on T cell-specific signaling pathways and the polarization of emerging T helper cells.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft-Versus-Host-Disease

Keywords

GVHD, Allogeneic, Hematopoietic Cell Transplant

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GVHD Regimen

Arm Type

Experimental

Arm Description

Graft versus host disease (GVHD) prophylaxis regimen IL-2 with Sirolimus and Tacrolimus after allogeneic hematopoietic cell transplant (HCT).

Intervention Type

Drug

Intervention Name(s)

IL-2

Other Intervention Name(s)

Proleukin®, (aldesleukin)

Intervention Description

A subcutaneous injection will be administered 3 times a week (separated by at least 1 day between injections), from day 0 to +90 (+/- 7 days).

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Intervention Description

Will be administered at 0.01 mg/kg/day (based on ideal body weight) continuous IV infusion or equivalent oral dosing starting on day -3

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

Rapamune

Intervention Description

Orally on day -1. The dose for loading is 12 mg by mouth (PO)

Primary Outcome Measure Information:

Title

Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT

Description

Time Frame

30 days post HCT

Secondary Outcome Measure Information:

Title

Overall Survival at Day +365

Description

Overall survival will be defined as the time from transplant date to death from any cause.

Time Frame

365 days post HCT

Title

Cumulative Incidence of Relapse

Description

Incidence of primary disease relapse per standard definitions.

Time Frame

1 year post HCT

Title

Cumulative Incidence of Grade II-IV Acute GVHD by Day +100

Description

Acute GVHD will be graded per the 1995 consensus guidelines.

Time Frame

100 days post HCT

Title

Cumulative Incidence of Chronic GVHD by Day +365

Description

Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria.

Time Frame

365 days post HCT

Title

Incidence of Non-relapse Death

Description

Incidence of Non-relapse death/Transplant-related mortality. Non-relapse death is defined as death in continuous remission from primary disease requiring transplantation.

Time Frame

365 days post HCT

Title

Incidence of Unexpected or Serious Adverse Events (AEs)

Description

Time Frame

Up to days 130 post HCT

Title

Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT

Description

The proportion of Tregs to non-Treg CD4+ cells to be assessed at day +90. Natural Killer Cells (NKs): Median K/uL NK cells.

Time Frame

90 days post HCT

Title

STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30

Description

Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +30.

Time Frame

30 days post HCT

Title

STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90

Description

Phosphorylation (p): pSTAT3, pSTAT5 (Y694), and pS6 among Treg and non-Treg at day +90.

Time Frame

90 days post HCT

Other Pre-specified Outcome Measures:

Title

Function of Blood Treg After Allogeneic HSCT

Description

Percent of Treg suppression at day +30. Investigators had also planned to test Treg function at day +90, if sufficient Tregs had been available for analysis.

Time Frame

30 days post HCT

Title

Rate of Natural Killer Cell (NK) Reconstitution

Description

Investigators planned to monitor natural killer cell (NK) reconstitution. Standard immune deficiency flow cytometry panels (IDP) was to be drawn on days +90, +180, and +365 to evaluate NK reconstitution. Results of standard lab tests to be compared to compiled data at a later date

Time Frame

365 days post HCT

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients must have an available 8/8 human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 matched-related or unrelated donor allogeneic hematopoietic peripheral blood stem cell graft. Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myeloproliferative neoplasms requiring a matched allogeneic HSCT. Acute Leukemia (AML or ALL) must be in complete remission defined as: <5% marrow blasts with no morphologic evidence of leukemia, no peripheral blasts, marrow >20% cellular, and peripheral absolute neutrophil count >1000/µL (platelet recovery is not required). Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have <5% marrow blasts. Myeloproliferative neoplasms (MPN): Must have <5% peripheral / marrow blasts. Adequate vital organ function: Left ventricular ejection fraction (LVEF) ≥ 45% by multi gated acquisition (MUGA) scan or ECHO Forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing lung capacity oxygenation (DLCO) ≥ 50% of predicted values on pulmonary function tests Transaminases (AST, ALT) < 2 times upper limit of normal values Creatinine clearance ≥ 50 cc/min. Performance status: Karnofsky Performance Status Score ≥ 80% Donor eligibility: Eligible donors will include healthy sibling, relative or unrelated donors that are matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing. Exclusion Criteria: Active infection not controlled with appropriate antimicrobial therapy History of HIV, hepatitis B, or hepatitis C infection Anti-thymocyte globulin, alemtuzumab, bortezomib, or cyclophosphamide administered within 14 days before or planned to receive with HCT conditioning or as part of GVHD prophylaxis in the 14 days after HCT. Hypersensitivity to recombinant human IL-2 Chronic lymphocytic leukemia, Hodgkin lymphoma, and non-hodgkin lymphoma are excluded as these malignancies may express the IL-2 receptor and pose a potential growth signal to any present disease. Sorror's co-morbidity factors with total score >4

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Brian Betts, MD

Organizational Affiliation

Moffitt Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

H. Lee Moffitt Cancer Center and Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

28104702

Citation

Betts BC, Pidala J, Kim J, Mishra A, Nishihori T, Perez L, Ochoa-Bayona JL, Khimani F, Walton K, Bookout R, Nieder M, Khaira DK, Davila M, Alsina M, Field T, Ayala E, Locke FL, Riches M, Kharfan-Dabaja M, Fernandez H, Anasetti C. IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation. Haematologica. 2017 May;102(5):948-957. doi: 10.3324/haematol.2016.153072. Epub 2017 Jan 19.

Results Reference

derived

Links:

URL

http://www.moffitt.org

Description

H. Lee Moffitt Cancer Center & Research Institute

URL

http://www.haematologica.org/content/early/2017/01/19/haematol.2016.153072.long

Description

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation

Learn more about this trial

In Vivo Treg Expansion and Graft-Versus-Host Disease Prophylaxis

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