Clinical trial NCT01927120: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft-Versus-Host-Disease
Keywords: GVHD
Allogeneic
Hematopoietic Cell Transplant
Lead sponsor: H. Lee Moffitt Cancer Center and Research Institute
Sponsor class: OTHER
First posted: 2013-08-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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:

  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

Primary outcomes:
measure: Regulatory T Cells (Tregs)/Total CD4+ Cells at Day 30 Post-HCT
timeFrame: 30 days post HCT
Secondary outcomes:
measure: Overall Survival at Day +365
timeFrame: 365 days post HCT
measure: Cumulative Incidence of Relapse
timeFrame: 1 year post HCT
measure: Cumulative Incidence of Grade II-IV Acute GVHD by Day +100
timeFrame: 100 days post HCT
measure: Cumulative Incidence of Chronic GVHD by Day +365
timeFrame: 365 days post HCT
measure: Incidence of Non-relapse Death
timeFrame: 365 days post HCT
measure: Incidence of Unexpected or Serious Adverse Events (AEs)
timeFrame: Up to days 130 post HCT
measure: Proportion of Treg Among Blood CD4+ T Cells at Day +90 After HCT
timeFrame: 90 days post HCT
measure: STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 30
timeFrame: 30 days post HCT
measure: STAT3, STAT5 (Y694), and S6 Phosphorylation Among Treg and Non-Treg at Day 90
timeFrame: 90 days post HCT
Other outcomes:
measure: Function of Blood Treg After Allogeneic HSCT
timeFrame: 30 days post HCT
measure: Rate of Natural Killer Cell (NK) Reconstitution
timeFrame: 365 days post HCT
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
Study officials:
affiliation: Moffitt Cancer Center
name: Brian Betts, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.