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

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

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).

Study Overview

• Status: Completed
• Conditions: Graft-Versus-Host-Disease
• Intervention / Treatment: Drug: IL-2; Drug: Tacrolimus; Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: IL-2; 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).; Other Names: Proleukin®; (aldesleukin); Drug: Tacrolimus; 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; Drug: Sirolimus; Orally on day -1. The dose for loading is 12 mg by mouth (PO); Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 days post HCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival at Day +365	Overall survival will be defined as the time from transplant date to death from any cause.	365 days post HCT
Cumulative Incidence of Relapse	Incidence of primary disease relapse per standard definitions.	1 year post HCT
Cumulative Incidence of Grade II-IV Acute GVHD by Day +100	Acute GVHD will be graded per the 1995 consensus guidelines.	100 days post HCT
Cumulative Incidence of Chronic GVHD by Day +365	Cumulative incidence of chronic GVHD by day +365 per NIH Consensus criteria.	365 days post HCT
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.	365 days post HCT
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.	Up to days 130 post HCT
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.	90 days post HCT
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.	30 days post HCT
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.	90 days post HCT

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Function of Blood Treg After Allogeneic HSCT	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.	30 days post HCT
Rate of Natural Killer Cell (NK) Reconstitution	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	365 days post HCT

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Investigators: Principal Investigator: Brian Betts, MD, Moffitt Cancer Center

Publications and helpful links

General Publications

• 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.

Helpful Links

• H. Lee Moffitt Cancer Center & Research Institute
• IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2014
• Primary Completion (Actual): August 25, 2016
• Study Completion (Actual): March 9, 2017

Study Registration Dates

• First Submitted: August 16, 2013
• First Submitted That Met QC Criteria: August 19, 2013
• First Posted (Estimate): August 22, 2013

Study Record Updates

• Last Update Posted (Actual): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 1, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Allogeneic; Hematopoietic Cell Transplant; GVHD
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Aldesleukin; Tacrolimus; Sirolimus
• Other Study ID Numbers: MCC-17578; NCI-2014-00755 (Other Identifier: NCI CTRP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No