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Inducible Regulatory T Cells (iTregs) in Non-Myeloablative Sibling Donor Peripheral Blood Stem Cell Transplantation

Primary Purpose

Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
iTreg
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 18 - 75 years of age with an HLA-identical sibling donor

  • One of the following disease categories:

    • Acute myelogenous leukemia - high risk CR1 (as evidenced by preceding MDS, intermediate to high risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery (ANC > 0.5x 109/L), AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
    • Acute lymphocytic leukemia - high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] or >1cycle to obtain CR; CR2+. All patients must be in CR as defined by hematological recovery (ANC > 0.5x 109/L), AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%.
    • Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible)
    • Non-Hodgkin lymphoma or Hodgkin lymphoma demonstrating chemosensitive disease
    • Myelodysplastic syndrome with severe pancytopenia, leading to either transfusion dependency or increased risk for infections
  • Performance status: Karnofsky ≥ 60%

  • Adequate organ function within 28 days of study enrollment defined as:

    • Liver: SGOT and SGPT < 5.0 x ULN; total bilirubin < 3 x ULN
    • Renal: serum creatinine < 2.0 mg/dl or glomerular filtration rate (GFR) > 40 mL/min/1.73m2. Patients with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have glomerular filtration rate (GFR) > 40 mL/min/1.73m2
    • Albumin: > 2.5 g/dL
    • Cardiac: No decompensated CHF or uncontrolled arrhythmia; ejection fraction > 35% within 6 weeks prior to study enrollment
    • Pulmonary: No O2 requirements; DLCO > 30% predicted within 6 weeks prior to study enrollment
  • If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease
  • Sexually active females of child bearing potential and males must agree to use effective contraception for the duration of the transplant period
  • Voluntary written consent

Exclusion Criteria:

  • Pregnancy or breast feeding - women of childbearing potential must have a negative pregnancy test within 28 days of study enrollment.
  • Prior myeloablative transplant within previous 3 months of study enrollment.
  • Evidence of HIV infection or known HIV positive serology.
  • Active serious infection.

Sites / Locations

  • Masonic Cancer Center, University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5 Extension

Arm Description

Administered 3 x 10^6 iTregs/kg infusion

Administered 3 x 10^7 iTregs/kg infusion

Administered 3 x 10^8 iTregs/kg infusion

Administered 10 x 10^8 iTregs/kg infusion

Administered 10 x 10^8 iTregs/kg or best available dose using sirolimus/MMF as graft-versus-host disease (GVHD) prophylaxis. Immunosuppression will consist of a combination of sirolimus and mycophenolate mofetil (MMF). Sirolimus will be administered starting at day -3 with 8mg-12mg oral loading dose followed by single dose 4 mg/day. MMF will be administered starting on day -3 at a dose of 3 gram/day divided in 2 or 3 doses. Intravenous (IV) route between days -3 and +5, then may change to PO between days +6 and +30. Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD.

Outcomes

Primary Outcome Measures

Incidence of grade 3-5 infusional toxicity
Targeted adverse events and unexpected events not explained by the PBSCT or disease will be collected [(1-4 hours after the iTreg infusion and before the PBSCT at day 0) and 24 hours and 48 hours after the iTreg infusion (+/- 2 hours)]

Secondary Outcome Measures

Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD)
Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Abstracted from the routine clinical data collected for the primary transplant protocol (MT2001-10).
Incidence of chronic graft-versus-host disease (GVHD)
Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Abstracted from the routine clinical data collected for the primary transplant protocol (MT2001-10).
Relapse of Disease
The return of signs and symptoms of a disease after a remission.
Survival
Number (count) of patients alive at 1 year after treatment.
Survival
Number (count) of patients alive at Day 100.

Full Information

First Posted
July 2, 2012
Last Updated
January 17, 2019
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT01634217
Brief Title
Inducible Regulatory T Cells (iTregs) in Non-Myeloablative Sibling Donor Peripheral Blood Stem Cell Transplantation
Official Title
Dose Escalation Study With Extension of Inducible Regulatory T Cells (iTregs) in Adult Patients Undergoing Non-Myeloablative HLA Identical Sibling Donor Peripheral Blood Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
November 8, 2013 (Actual)
Primary Completion Date
December 1, 2017 (Actual)
Study Completion Date
December 1, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase I single center dose escalation study with an extension at the best available dose to determine the tolerability of inducible regulatory T cells (iTregs) when given to adult patients undergoing non-myeloablative HLA-identical sibling donor peripheral blood stem cell (PBSC) transplantation for the treatment of a high risk malignancy. Up to 5 dose cohorts will be tested. Once the tolerable dose is determined for iTregs, enrollment will continue with an additional 10 patients using sirolimus/Mycophenolate mofetil (MMF) graft-versus-host disease (GVHD) prophylaxis to gain further safety information and to provide pilot data in this treatment setting.
Detailed Description
Co-enrollment in University Of Minnesota protocol MT2001-10 is required and transplantation will be according to that protocol with iTregs administered the morning of day 0 followed no sooner than 4 hours later by the PBSC transplantation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Multiple Myeloma, Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Administered 3 x 10^6 iTregs/kg infusion
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Administered 3 x 10^7 iTregs/kg infusion
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Administered 3 x 10^8 iTregs/kg infusion
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Administered 10 x 10^8 iTregs/kg infusion
Arm Title
Cohort 5 Extension
Arm Type
Experimental
Arm Description
Administered 10 x 10^8 iTregs/kg or best available dose using sirolimus/MMF as graft-versus-host disease (GVHD) prophylaxis. Immunosuppression will consist of a combination of sirolimus and mycophenolate mofetil (MMF). Sirolimus will be administered starting at day -3 with 8mg-12mg oral loading dose followed by single dose 4 mg/day. MMF will be administered starting on day -3 at a dose of 3 gram/day divided in 2 or 3 doses. Intravenous (IV) route between days -3 and +5, then may change to PO between days +6 and +30. Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD.
Intervention Type
Biological
Intervention Name(s)
iTreg
Intervention Description
The iTregs will be infused at the assigned dose without a filter or pump slowly by gravity over 15-60 minutes. The iTregs should be given at least 4 hours before the peripheral blood stem cell (PBSC) infusion (MT2001-10).
Primary Outcome Measure Information:
Title
Incidence of grade 3-5 infusional toxicity
Description
Targeted adverse events and unexpected events not explained by the PBSCT or disease will be collected [(1-4 hours after the iTreg infusion and before the PBSCT at day 0) and 24 hours and 48 hours after the iTreg infusion (+/- 2 hours)]
Time Frame
Within 48 Hours After iTregs Administration
Secondary Outcome Measure Information:
Title
Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD)
Description
Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Abstracted from the routine clinical data collected for the primary transplant protocol (MT2001-10).
Time Frame
Day 100
Title
Incidence of chronic graft-versus-host disease (GVHD)
Description
Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Abstracted from the routine clinical data collected for the primary transplant protocol (MT2001-10).
Time Frame
12 Months
Title
Relapse of Disease
Description
The return of signs and symptoms of a disease after a remission.
Time Frame
12 Months
Title
Survival
Description
Number (count) of patients alive at 1 year after treatment.
Time Frame
1 Year
Title
Survival
Description
Number (count) of patients alive at Day 100.
Time Frame
Day 100

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 18 - 75 years of age with an HLA-identical sibling donor One of the following disease categories: Acute myelogenous leukemia - high risk CR1 (as evidenced by preceding MDS, intermediate to high risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery (ANC > 0.5x 109/L), AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Acute lymphocytic leukemia - high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] or >1cycle to obtain CR; CR2+. All patients must be in CR as defined by hematological recovery (ANC > 0.5x 109/L), AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in chronic phase is eligible) Non-Hodgkin lymphoma or Hodgkin lymphoma demonstrating chemosensitive disease Myelodysplastic syndrome with severe pancytopenia, leading to either transfusion dependency or increased risk for infections Performance status: Karnofsky ≥ 60% Adequate organ function within 28 days of study enrollment defined as: Liver: SGOT and SGPT < 5.0 x ULN; total bilirubin < 3 x ULN Renal: serum creatinine < 2.0 mg/dl or glomerular filtration rate (GFR) > 40 mL/min/1.73m2. Patients with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have glomerular filtration rate (GFR) > 40 mL/min/1.73m2 Albumin: > 2.5 g/dL Cardiac: No decompensated CHF or uncontrolled arrhythmia; ejection fraction > 35% within 6 weeks prior to study enrollment Pulmonary: No O2 requirements; DLCO > 30% predicted within 6 weeks prior to study enrollment If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy and responsive disease and be cleared by Infectious Disease Sexually active females of child bearing potential and males must agree to use effective contraception for the duration of the transplant period Voluntary written consent Exclusion Criteria: Pregnancy or breast feeding - women of childbearing potential must have a negative pregnancy test within 28 days of study enrollment. Prior myeloablative transplant within previous 3 months of study enrollment. Evidence of HIV infection or known HIV positive serology. Active serious infection.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Margaret MacMillan, MD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33666654
Citation
MacMillan ML, Hippen KL, McKenna DH, Kadidlo D, Sumstad D, DeFor TE, Brunstein CG, Holtan SG, Miller JS, Warlick ED, Weisdorf DJ, Wagner JE, Blazar BR. First-in-human phase 1 trial of induced regulatory T cells for graft-versus-host disease prophylaxis in HLA-matched siblings. Blood Adv. 2021 Mar 9;5(5):1425-1436. doi: 10.1182/bloodadvances.2020003219.
Results Reference
derived

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Inducible Regulatory T Cells (iTregs) in Non-Myeloablative Sibling Donor Peripheral Blood Stem Cell Transplantation

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