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

Phase 2

Terminated

Conditions: Natural Killer Cell Malignancies
Chronic Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Acute Lymphoblastic Leukemia
Large-cell Lymphoma
Prolymphocytic Leukemia
Hodgkin Lymphoma
Burkitt Lymphoma
Myelodysplastic Syndromes
Follicular Lymphoma

Interventions: Biological: Infusion of Treg

Registration Number: NCT02991898

Lead Sponsor: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treg Infusion	Infusion of Treg	The Treg cell infusion is given no sooner than 1 hour, but within 24 hours after the 2nd cord blood infusion

Primary Outcome Measures

Name	Time	Method
Number of Participants Survived	2 years	Count of patients who survived 2 years post intervention

Secondary Outcome Measures

Name	Time	Method
Percentage of Donor Cell Chimerism	Day +100	The incidence of chimerism in patients treated
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.
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.
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.
Number of Participant With Detectable Treg Cells at d14	14 days	The proportion of patients with detectable Treg cells at day 14 post infusion
Number of Participants Experiencing Treg Cell Infusion Toxicity	48 hours post infusion	Incidence of Adverse Events
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
Number of Participants With Grade II-IV aGVHD	Assessed weekly until day 100, then day 180, 360	Probability of grade II-IV aGVHD
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.
Length of Treg Survival	24 hours post infusion	Length of Treg survival after infusion of Treg.
Number of Participants Survived One Year Post-transplant	1 year	The probability of survival, one year post-treatment
Number of Participants With Platelet Recovery	1 year	The incidence of platelet recovery (return of platelet counts to \> 20,000/μL) in treated patients
Number of Participants With Chronic GVHD	1 year	The incidence of chronic GVHD in treated patients after one year