Adoptive TReg Cell for Suppression of aGVHD After UCB HSCT for Heme Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02991898
Recruitment Status : Suspended (Safety)
First Posted : December 14, 2016
Last Update Posted : March 29, 2018
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Brief Summary:
This is a single center pilot study of a non-myeloablative umbilical cord blood transplant for the treatment of a hematological malignancy with a single infusion of T regulatory (Treg) given shortly after UCB transplantation.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Burkitt Lymphoma Natural Killer Cell Malignancies Chronic Myelogenous Leukemia Myelodysplastic Syndromes Large-cell Lymphoma Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Marginal Zone B-Cell Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle-Cell Lymphoma Prolymphocytic Leukemia Hodgkin Lymphoma Multiple Myeloma Acute Myelogenous Leukemia Biphenotypic Leukemia Undifferentiated Leukemia Biological: Infusion of Treg Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adoptive Transfer of T Regulatory Cell for Suppression of Acute Graft-vs-Host-Disease After an Umbilical Cord Blood Transplant for Hematologic Malignancies
Actual Study Start Date : February 16, 2017
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025

Arm Intervention/treatment
Experimental: Treg Infusion
The Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
Biological: Infusion of Treg

Allopurinol on day -7 to day 0 Cyclophosphamide 50 mg/kg IV over 2 hours on day -6 Fludarabine 30mg/m2 IV over 1 hour on day -6, -5, -4, -3, and -2 Total Body Irradiation 200 cGy as a single dose

Sirolimus 8mg-12mg oral loading dose followed by signle dose 4mg/day. Levels are to be monitored 3 times/week in the first week, weekly until day +60, and as clinically indicated until day +100 post-transplantation.

Mycophenolate Mofetil (MMF) 3 gram/day IV/PO divided in 2 or 3 doses. Stop MMF at day +30 or 7 days after neutrophil recovery, whichever day is later, if no acute GVHD.

DUCBT followed Tregs - double umbilical cord blood transplant (FIRST) followed by the Treg cell infusion (SECOND) no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion.

Other Name: T regulatory cells

Primary Outcome Measures :
  1. Efficacy of Intervention [ Time Frame: 2 years ]
    Measured by the length of Treg survival after infusion of Treg

Secondary Outcome Measures :
  1. Grade II-IV aGVHD [ Time Frame: Assessed weekly until day 100, then day 180, 360 ]
    Probability of grade II-IV aGVHD

  2. Grade III-IV aGVHD [ Time Frame: Assessed weekly until day 100, then day 180, 360 ]
    Probability of grade III-IV aGVHD

  3. Treatment related mortality (TRM) [ Time Frame: 6 months ]
    Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

  4. Relapse [ Time Frame: 1 year ]
    Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

  5. Incidence of viral and fungal infections [ Time Frame: 1 year ]
    Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

  6. Detectable Treg cells [ Time Frame: Day 14 ]
    The proportion of patients with detectable Treg cells at day 14 post infusion

  7. Immune reconstitution [ Time Frame: Assessed at Day 4, weekly for 8 weeks ]
    The proportion of patients with immune reconstitution. Continuous endpoints will be described by medians, ranges and interquartile ranges as well as means and standard deviations if normally distributed.

  8. Toxicity [ Time Frame: 48 hours post infusion ]
    Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for Adverse Events V 4.0 (CTCAE).

  9. Treg Survival [ Time Frame: 24 hours post infusion ]
    Length of Treg survival after infusion of Treg.

  10. Chimerism [ Time Frame: Day +100 ]
    The incidence of chimerism in patients treated

  11. Survival [ Time Frame: 1 year ]
    The probability of survival, one year post-treatment

  12. Neutrophil Recovery [ Time Frame: Day 42 ]
    The incidence of neutrophil recovery in treated patients

  13. Platelet Recovery [ Time Frame: 1 year ]
    The incidence of platelet recovery in treated patients

  14. Chronic GVHD [ Time Frame: 1 year ]
    The incidence of chronic GVHD in treated patients after one year

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Disease Criteria:

  • Acute Leukemias: Must be in remission by morphology (around 5% blasts but < 20% blasts by morphology). Also a small percentage of blasts that is equivocal between marrow regeneration versus early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse.

    • Acute Lymphoblastic Leukemia (ALL) second or greater CR; CR1 unable to tolerate consolidation chemotherapy due to chemotherapy-related toxicities; CR1 high-risk ALL.
    • High risk ALL is defined as having one of the following:

      • Evidence of high risk cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL rearrangements, IKZF1
      • 30 years of age or older at diagnosis
      • White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL) at diagnosis
      • CNS leukemia involvement during the course of disease
      • Slow cytologic response (>10% lymphoblasts in bone marrow on Day 14 of induction therapy)
      • Evidence of persistent immonophenotypic or molecular minimal residual disease (MRD) at the end of induction and consolidation therapy
    • Acute Myelogenous Leukemia (AML) and related precursor neoplasms: 2nd or greater complete remission (CR); first complete remission (CR1) in patients > 60 years old; CR1 in ≤ 60 years old that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following:

      • t(8,21) without cKIT mutation
      • inv(16) or t(16;16) without cKIT mutation
      • Normal karyotype with mutated NPM1 and wild type FLT-ITD
      • Normal karyotype with double mutated CEBPA
      • Acute prolymphocytic leukemia (APL) in first molecular remission at end of consolidation
    • Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
  • Burkitt's Lymphoma in CR2 or subsequent CR
  • Natural Killer Cell Malignancies
  • Chronic Myelogenous Leukemia: all types except refractory blast crisis. Chronic phase patients must have failed at least two different tyrosine-kinase inhibitors (TKIs), or been intolerant to all available TKIs or have T315I mutation.
  • Myelodysplastic Syndrome: IPSS INT-2 or High Risk; R-IPSS High or Very High; WHO classification: RAEB-1, RAEB-2; Severe Cytopenias: ANC < 0.8, Anemia or thrombocytopenia requiring transfusion; Poor or very poor risk cytogenetics based on IPSS or R-IPSS definitions; therapy-related MDS. Blasts must be < 5% by bone marrow aspirate morphology. If ≥5% blasts, patient requires chemotherapy for cytoreduction to <5% blasts prior to transplantation.
  • Large-Cell Lymphoma, Hodgkin Lymphoma and Multiple Myeloma with chemotherapy sensitive disease that has failed or patients who are ineligible for an autologous transplant.
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone B-Cell Lymphoma, Follicular Lymphoma, which have progressed within 12 months of achieving a partial or complete remission. Patients who had remissions lasting > 12 months are eligible after at least two prior therapies. Patients with bulky disease should be considered for debulking chemotherapy before transplant. Patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month.
  • Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia are eligible after initial therapy if chemotherapy sensitive.
  • Patients must have undergone an autologous transplant ≤ 12 months prior to transplant on this study or have received multi-agent or immunosuppressive chemotherapy within 3 months of the preparative regimen.

Performance Status, Organ Function, Contraception Use

  • Karnofsky score ≥ 70% (Appendix II)
  • Adequate organ function within 14 days (30 days for cardiac and pulmonary) of registration on-study defined as:

    • Renal: creatinine ≤ 2.0 mg/dL, for patient with a creatinine > 1.2 mg/dL or a history of renal dysfunction an estimated glomerular filtration rate ≥ 40 mL/min/1.73 m2 is required
    • ALT, AST and alkaline phosphatase ≤ 5 x upper limit of normal and total bilirubin ≤ 2.5 mg/dL except for patients with Gilbert's syndrome or hemolysis
    • Pulmonary function: DLCO, FEV1, FVC ≥ 40% predicted, and absence of O2 requirements.
    • Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction ≥ 40%.
  • Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment.
  • Voluntary written consent

Inclusion Criteria:

  • Must be ≥18, but < 70 years of age with no available medically suitable 7/8 or 8/8 sibling donor - patients ≥ 70 and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2(
  • UCB unit(s) composing the graft will be selected according to the current University of Minnesota umbilical cord blood graft selection algorithm plus an additional cord blood unit to be used as the source to manufacture the Treg product. This UCB unit must be matched at 4-6/6 to the patient, considering HLA-A, B at the antigen level and DRB1 at the allele level.

Exclusion Criteria:

  • Untreated active infection
  • History of HIV infection
  • Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
  • Prior allogeneic transplantation
  • Less than 3 months from myeloablative conditioning for autologous transplantation (if applicable)
  • Evidence of progressive disease by imaging modalities or biopsy - persistent PET activity, though possibly related to lymphoma, is not an exclusion criterion in the absence of CT changes indicating progression.
  • CML in blast crisis
  • Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressing on salvage therapy.
  • Active central nervous system malignancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02991898

United States, Minnesota
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Principal Investigator: Claudio Brunstein, MD, PhD Masonic Cancer Center, University of Minnesota

Responsible Party: Masonic Cancer Center, University of Minnesota Identifier: NCT02991898     History of Changes
Other Study ID Numbers: 2016LS107
MT2016-17 ( Other Identifier: University of Minnesota Blood and Marrow Transplant Program )
First Posted: December 14, 2016    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Masonic Cancer Center, University of Minnesota:

Additional relevant MeSH terms:
Multiple Myeloma
Lymphoma, Follicular
Myelodysplastic Syndromes
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid
Lymphoma, B-Cell
Hodgkin Disease
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Burkitt Lymphoma
Lymphoma, B-Cell, Marginal Zone
Leukemia, Myeloid, Acute
Leukemia, Prolymphocytic
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases