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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Multiple Myeloma, Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: iTreg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Administered 3 x 10^6 iTregs/kg infusion | Biological: iTreg<br>* 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).<br>|
| Experimental: Cohort 2<br>Administered 3 x 10^7 iTregs/kg infusion | Biological: iTreg<br>* 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).<br>|
| Experimental: Cohort 3<br>Administered 3 x 10^8 iTregs/kg infusion | Biological: iTreg<br>* 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).<br>|
| Experimental: Cohort 4<br>Administered 10 x 10^8 iTregs/kg infusion | Biological: iTreg<br>* 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).<br>|
| Experimental: Cohort 5 Extension<br>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. | Biological: iTreg<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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)] | Within 48 Hours After iTregs Administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 100 | 
| 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). | 12 Months | 
| Relapse of Disease | The return of signs and symptoms of a disease after a remission. | 12 Months | 
| Survival | Number (count) of patients alive at 1 year after treatment. | 1 Year | 
| Survival | Number (count) of patients alive at Day 100. | Day 100 |