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

Phase 1

Completed

• Conditions: Multiple Myeloma; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia
• Interventions: Biological: iTreg

• Registration Number: NCT01634217
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

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.

Study Timeline

• Study First Submitted: 2012-07-02
• Study First Submitted QC: 2012-07-05
• Study First Posted: 2012-07-06
• Study Start: 2013-11-08
• Primary Completion: 2017-12-01
• Study Completion: 2018-12-01
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-17
• Last Update Posted: 2019-01-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 4	iTreg	Administered 10 x 10\^8 iTregs/kg infusion
Cohort 1	iTreg	Administered 3 x 10\^6 iTregs/kg infusion
Cohort 3	iTreg	Administered 3 x 10\^8 iTregs/kg infusion
Cohort 5 Extension	iTreg	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.
Cohort 2	iTreg	Administered 3 x 10\^7 iTregs/kg infusion

Primary Outcome Measures

Name	Time	Method
Incidence of grade 3-5 infusional toxicity	Within 48 Hours After iTregs Administration	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

Name	Time	Method
Cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD)	Day 100	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)	12 Months	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	12 Months	The return of signs and symptoms of a disease after a remission.
Survival	Day 100	Number (count) of patients alive at Day 100.

Trial Locations

Locations (1)

Masonic Cancer Center, University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States