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

Sponsor
Masonic Cancer Center, University of Minnesota (Other)
Overall Status
Terminated
CT.gov ID
NCT02991898
Collaborator
(none)
3
Enrollment
1
Location
1
Arm
28.1
Actual Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
N/A
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 :
Feb 16, 2017
Actual Primary Completion Date :
Jun 20, 2019
Actual Study Completion Date :
Jun 20, 2019

Arms and Interventions

ArmIntervention/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 single 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 Names:
  • T regulatory cells
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Survived [2 years]

      Count of patients who survived 2 years post intervention

    Secondary Outcome Measures

    1. Number of Participants With Grade II-IV aGVHD [Assessed weekly until day 100, then day 180, 360]

      Probability of grade II-IV aGVHD

    2. Number of Participants Experiencing Treatment Related Mortality (TRM) [6 months]

      Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

    3. Number of Participants Who Experienced Relapse [1 year]

      Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

    4. Number of Participants With Incidence of Bacterial, Viral and Fungal Infections [1 year]

      Evaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.

    5. Number of Participant With Detectable Treg Cells at d14 [14 days]

      The proportion of patients with detectable Treg cells at day 14 post infusion

    6. Number of Participants With Immune Reconstitution [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.

    7. Number of Participants Experiencing Treg Cell Infusion Toxicity [48 hours post infusion]

      Incidence of Adverse Events

    8. Length of Treg Survival [24 hours post infusion]

      Length of Treg survival after infusion of Treg.

    9. Percentage of Donor Cell Chimerism [Day +100]

      The incidence of chimerism in patients treated

    10. Number of Participants Survived One Year Post-transplant [1 year]

      The probability of survival, one year post-treatment

    11. Number of Participants With Neutrophil Recovery [Day 42]

      The incidence of neutrophil recovery, that is return of neutrophil counts to ≥ 5 X 10^8/L in treated patients

    12. Number of Participants With Platelet Recovery [1 year]

      The incidence of platelet recovery (return of platelet counts to > 20,000/μL) in treated patients

    13. Number of Participants With Chronic GVHD [1 year]

      The incidence of chronic GVHD in treated patients after one year

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Must be ≥18, but < 70 years of age with no matched 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 (http://www.qxmd.com/calculate-online/hematology/hct-ci)

    • UCB unit(s) composing the graft will be selected according to the current University of Minnesota umbilical cord blood graft selection algorithm and 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

    • Acute Leukemias: Must be in remission 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. Refer to Section 5.2 for complete definitions.

    • 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 be < 5%, preferably < 20% blasts by morphology by bone marrow aspirate morphology.. If ≥ 5% blasts, chemotherapy for cytoreduction to <5% blasts prior to transplantation may be considered.

    • Chronic myeloid neoplasms, including but not limited to CMML with blasts must around 5% blasts, preferably < 20% blasts by morphology by bone marrow aspirate morphology. If ≥5% blasts, chemotherapy for cytoreduction to <5% blasts prior to transplantation may be considered.

    • 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

    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Masonic Cancer Center at University of MinnesotaMinneapolisMinnesotaUnited States55455

    Sponsors and Collaborators

    • Masonic Cancer Center, University of Minnesota

    Investigators

    • Principal Investigator: Claudio Brunstein, MD, PhD, Masonic Cancer Center, University of Minnesota

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT02991898
    Other Study ID Numbers:
    • 2016LS107
    • MT2016-17
    First Posted:
    Dec 14, 2016
    Last Update Posted:
    Sep 29, 2020
    Last Verified:
    Sep 1, 2020

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Period Title: Overall Study
    STARTED3
    COMPLETED3
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Overall Participants3
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    2
    66.7%
    >=65 years
    1
    33.3%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    Male
    3
    100%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    3
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    3
    100%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    3
    100%

    Outcome Measures

    1. Primary Outcome
    TitleNumber of Participants Survived
    DescriptionCount of patients who survived 2 years post intervention
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    1
    33.3%
    2. Secondary Outcome
    TitleNumber of Participants With Grade II-IV aGVHD
    DescriptionProbability of grade II-IV aGVHD
    Time FrameAssessed weekly until day 100, then day 180, 360

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    2
    66.7%
    3. Secondary Outcome
    TitleNumber of Participants Experiencing Treatment Related Mortality (TRM)
    DescriptionEvaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
    Time Frame6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    0
    0%
    4. Secondary Outcome
    TitleNumber of Participants Who Experienced Relapse
    DescriptionEvaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    1
    33.3%
    5. Secondary Outcome
    TitleNumber of Participants With Incidence of Bacterial, Viral and Fungal Infections
    DescriptionEvaluated with descriptive statistics and plots or cumulative incidence curves if enough evaluable patients are available for time-to-event endpoints.
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Bacterial
    1
    33.3%
    Viral
    2
    66.7%
    Fungal
    0
    0%
    6. Secondary Outcome
    TitleNumber of Participant With Detectable Treg Cells at d14
    DescriptionThe proportion of patients with detectable Treg cells at day 14 post infusion
    Time Frame14 days

    Outcome Measure Data

    Analysis Population Description
    Samples were not analyzed, and so data not available for reporting.
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants0
    7. Secondary Outcome
    TitleNumber of Participants With Immune Reconstitution
    DescriptionThe 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.
    Time FrameAssessed at Day 4, weekly for 8 weeks

    Outcome Measure Data

    Analysis Population Description
    Samples were not analyzed, and so data not available for reporting.
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants0
    8. Secondary Outcome
    TitleNumber of Participants Experiencing Treg Cell Infusion Toxicity
    DescriptionIncidence of Adverse Events
    Time Frame48 hours post infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    2
    66.7%
    9. Secondary Outcome
    TitleLength of Treg Survival
    DescriptionLength of Treg survival after infusion of Treg.
    Time Frame24 hours post infusion

    Outcome Measure Data

    Analysis Population Description
    Samples were not analyzed, and so data not available for reporting.
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants0
    10. Secondary Outcome
    TitlePercentage of Donor Cell Chimerism
    DescriptionThe incidence of chimerism in patients treated
    Time FrameDay +100

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Mean (Full Range) [percentage of donor cells]
    72
    11. Secondary Outcome
    TitleNumber of Participants Survived One Year Post-transplant
    DescriptionThe probability of survival, one year post-treatment
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    2
    66.7%
    12. Secondary Outcome
    TitleNumber of Participants With Neutrophil Recovery
    DescriptionThe incidence of neutrophil recovery, that is return of neutrophil counts to ≥ 5 X 10^8/L in treated patients
    Time FrameDay 42

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    2
    66.7%
    13. Secondary Outcome
    TitleNumber of Participants With Platelet Recovery
    DescriptionThe incidence of platelet recovery (return of platelet counts to > 20,000/μL) in treated patients
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    2
    66.7%
    14. Secondary Outcome
    TitleNumber of Participants With Chronic GVHD
    DescriptionThe incidence of chronic GVHD in treated patients after one year
    Time Frame1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    Measure Participants3
    Count of Participants [Participants]
    0
    0%

    Adverse Events

    Time Frame1 week
    Adverse Event Reporting Description
    Arm/Group TitleTreg Infusion
    Arm/Group DescriptionThe Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion
    All Cause Mortality
    Treg Infusion
    Affected / at Risk (%)# Events
    Total2/3 (66.7%)
    Serious Adverse Events
    Treg Infusion
    Affected / at Risk (%)# Events
    Total2/3 (66.7%)
    Immune system disorders
    Graft Versus Host Disease2/3 (66.7%) 2
    Vascular disorders
    Capillary leak syndrome1/3 (33.3%) 1
    Cytokine release syndrome1/3 (33.3%) 1
    Other (Not Including Serious) Adverse Events
    Treg Infusion
    Affected / at Risk (%)# Events
    Total2/3 (66.7%)
    Cardiac disorders
    Hypertension1/3 (33.3%) 7
    General disorders
    Chills1/3 (33.3%) 2
    Edema Limbs1/3 (33.3%) 4
    Fatigue1/3 (33.3%) 2
    Febrile neutropenia1/3 (33.3%) 3
    Fever1/3 (33.3%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleClaudio Brunstein
    OrganizationMasonic Cancer Center, University of Minnesota
    Phone612-625-3918
    Emailbruns072@umn.edu
    Responsible Party:
    Masonic Cancer Center, University of Minnesota
    ClinicalTrials.gov Identifier:
    NCT02991898
    Other Study ID Numbers:
    • 2016LS107
    • MT2016-17
    First Posted:
    Dec 14, 2016
    Last Update Posted:
    Sep 29, 2020
    Last Verified:
    Sep 1, 2020