T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

Study Overview
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Brief Summary
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This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD). In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.

Detailed Description
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Based on prior studies, the first patient will start at lowest dose combination (3 x 10^6/kg of Treg and 3 x 10^6/kg of CD3+ Teff cells). One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a successful step, then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a failed step, then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations. An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.

Official Title
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Optimization of the T Regulatory Cell and T Effector Cell Doses in Recipients of Double UCB Transplantation for Treatment of Hematological Malignancies

Conditions
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Hematologic Malignancy, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia in Blast Crisis, Anemia, Refractory, With Excess of Blasts, Chronic Myeloproliferative Disease, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Marginal Zone B-cell Lymphoma, Follicular Lymphoma, Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Lymphoma, Large Cell Non-Hodgkin's Lymphoma, Lymphoblastic Lymphoma, Burkitt's Lymphoma, High Grade Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Biological: Treg cells
* Biological: CD3+ Teff cells
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Radiation: Total body irradiation
* Biological: Umbilical cord blood transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Only patients requiring a double umbilical cord blood (UCB) transplant are to be considered for this study. UCB Requirements Three UCB units are required - one for Treg production and two for UCB transplant. The unrelated UCB donors must be 4-6/6 HLA-A, B, DRB1 matched with the recipient (HLA matching using molecular techniques: A and B to antigen level resolution and DR to allele level resolution). Suitable UCB units will be selected according to the University Of Minnesota UCB Graft Selection Algorithm. Suitable UCB units must be ABO matched. Disease Criteria: Patients aged 18 to 55 years Acute Myeloid Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy (if patient refuses or is disqualified from alternative protocols), or in 3rd or higher complete remission (CR). Acute Lymphocytic Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy, or in 3rd or higher CR Chronic Myelogenous Leukemia in Blast Crisis: with ≤10% residual blasts in the bone marrow aspirate after at least 1 cycle of induction chemotherapy in combination with a tyrosine kinase inhibitor (TKI) Refractory Anemia with Excess Blasts: (≤ 10%) in representative bone marrow aspirate sample of blasts after 1 cycle of induction chemotherapy. If treated with hypomethylating agents, patients are eligible if blast count is ≤ 10% after 4 cycles or evidence of stable or progressive disease after at least 2 cycles. Chronic Myeloproliferative Disease Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone B-Cell Lymphoma or Follicular Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm Large Cell Non-Hodgkin's Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other High-Grade NHL: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm Performance Status, Age, and Organ Function Adequate performance status defined as a Karnofsky score ≥ 80% Adequate organ function defined as: Renal: creatinine < 2.0 mg/dL, Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal, Pulmonary function: DLCOcorr > 50% normal, Cardiac: left ventricular ejection fraction > 45% Voluntary written informed consent signed before performance of any study-related procedure not part of normal medical care Exclusion Criteria: Available medically suitable HLA-identical related donor Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days) 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 myeloablative transplant within the last 6 months Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar) as part of their salvage therapy (not eligible for myeloablative umbilical cord blood transplant)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treg Plus CD3+Teff Treatment<br>Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation | Biological: Treg cells<br>* Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10^6/kg, 10 x 10^6/kg, 30 x 10^6/kg, 100 x 10^6/kg and 300 x 10^6/kg)<br>Biological: CD3+ Teff cells<br>* Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10^6 cells/kg, 6 x 10^6 cells/kg, 9 x 10^6 cells/kg, 12 x 10^6 cells/kg, and 15 x 10^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts<br>Drug: Fludarabine<br>* Given intravenously on Days -8 through -6, 25 mg/m^2 over 1 hour<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Given intravenously on Day -7 and -6, 60 mg/kg<br>* Other names: Cytoxan;Radiation: Total body irradiation<br>* Given on Days -4 through -2, 165 cGY twice a day.<br>Biological: Umbilical cord blood transplantation<br>* Infusion given on day 0<br>* Other names: UCBT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Optimal Cell Dose Mixture | Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD | Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine incidence of infusional toxicity | reaction that occurs with 48 hours of product infusion | 48 hours | 
| Incidence of neutrophil recovery | Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42 | Day 42 | 
| Incidence of double and single chimerism | Determine incidence of double and single unit chimerism at various time points | Day +21, Day +180, 1 Year | 
| Incidence of Viral and Fungal Infections | Determine incidence of viral and fungal infections at 1 year | 1 Year | 
| 1 Year Survival | Estimate the probability of survival at 1 year | 1 Year | 
| Incidence of Grade III-IV Acute Graft-Versus-Host Disease | Determine the incidence of grade III-IV acute GVHD at day 100 | Day 100 | 
| Incidence of Treatment Related Death | Determine the incidence of treatment related mortality (TRM) at 6 months | 6 Months | 
| Incidence of Platelet Recovery | Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year | 1 Year | 
| Incidence of Chronic Graft-Versus-Host Disease | Determine the incidence of chronic GVHD at 1 year | 1 Year | 
| Incidence of Relapse | Determine the incidence of relapse at 1 year | 1 Year |