T-Regulatory Cell Infusion Post Umbilical Cord Blood Transplant in Patients With Advanced Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood transplant helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T-regulatory cells after the transplant may decrease this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. However, the donor immune system may also react against the recipient's tissues (graft-versus-host disease). PURPOSE: This phase I trial is studying the side effects and best dose of donor T-regulatory cells after an umbilical cord blood transplant in treating patients with advanced hematologic cancer or other disorder.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells. Secondary Estimate the proportion of patients with detectable circulating Treg cells at 0, 1, 3, 7, and 14 days after infusion. Estimate the risk of grades II-IV and III-IV acute graft versus host disease (GVHD) at day +100 with the infusion of Treg cells. Estimate the proportion of patients with sustained donor engraftment. Estimate the proportion of patients with double chimerism at 6 months and 1 year. Determine the speed and cumulative incidence of neutrophil recovery by day 42 and platelet recovery by 6 months after UCB transplantation. Estimate the risk of chronic GVHD at 1 year. Estimate the probability of disease-free survival at 100 days and 1 year. Estimate the risk of fungal and viral infections at 1 year Estimate the risk of relapse at 1 year Characterize the pattern of immune cell recovery over 1 year OUTLINE: This is a dose-escalation study of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells. Patients receive nonmyeloablative UCB transplantation and post-transplant immunosuppression as in protocol UMN-2005LS036 (without antithymocyte globulin during conditioning regimen). Nonmyeloablative conditioning and UCB transplantation: Patients receive allopurinol on days -7 to day 0, fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6; undergo total-body irradiation (TBI) once on day -1; and undergo UCB transplantation on day 0. Immunosuppression therapy: Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180. Patients also receive mycophenolate mofetil IV or orally every 8 hours on days -3 to +30. Radiation therapy: total body irradiation is administered on Day -1 of 200 cGy. UCB Treg cell infusion: Patients receive escalating doses of UCB-derived CD4+ CD25+ Treg cells IV on day +1 (and Day +15 for dose level 5 only) until the maximum tolerated dose is obtained. After completion of study treatment, patients are followed at day 180, 360, and 720.

Official Title
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Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation

Conditions
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Leukemia, Lymphoma, Multiple Myeloma, Plasma Cell Neoplasm, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: umbilical cord blood transplantation
* Drug: Allopurinol
* Drug: fludarabine phosphate
* Drug: Cyclophosphamide
* Radiation: Total body irradiation
* Biological: Treg infusion
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18 to 75 years old Eligible for and co-enrolled on protocol UMN-2005LS036, for treatment of any of the following advanced hematologic malignancies: Acute leukemias in complete remission (high risk CR1 or subsequent CR); chronic myelogenous leukemia (except refractory blast crisis); myelodysplastic syndrome with severe pancytopenia or complex cytogenetics, large-cell lymphoma, Hodgkin's lymphoma and multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone b-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia may be eligible after initial therapy. Have three partially HLA matched umbilical cord blood (UCB) units (1-2 units for UCB transplantation per MT2005-02 and 1 unit for the Treg cell infusion.) Adequate organ function Exclusion Criteria: Patients not exposed to highly immunosuppressive single agent or multi-agent chemotherapy within 3 months, or an ablative preparative regimen for autologous hematopoietic stem cell transplant (HCT) within 1 year. Pregnancy or breastfeeding Current active serious infection Evidence of human immunodeficiency virus (HIV) or known HIV positive serology Patients with acute leukemia in morphologic relapse/persistent disease defined as >5% blasts in a > or = 15% cellular bone marrow or any % blasts if blasts have unique morphologic markers (e.g., Auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible. Chronic myelogenous leukemia in refractory blast crisis. Active central nervous system malignancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UCB post-transplant Treg Cell Infusion<br>Includes patients with high risk malignancy receiving allopurinol, fludarabine phosphate, cyclophosphamide, sirolimus, total body irradiation, double umbilical cord blood transplantation and Treg infusion cells after transplant. Patients will receive differing dose levels as they are entered and assigned to determine the maximum tolerated dose. | Biological: umbilical cord blood transplantation<br>* Infusion of umbilical cord blood<br>* Other names: UCB transplant;Drug: Allopurinol<br>* Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.<br>* Other names: Zyloprim;Drug: fludarabine phosphate<br>* 40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 50 mg/kg intravenous over 2 hours on Day -6<br>* Other names: Cytoxan;Radiation: Total body irradiation<br>* 200 cGy on Day -1<br>* Other names: radiation;Biological: Treg infusion<br>* Infusion of T regulatory cells on Day +1 (also Day +15 for Dose level 5 only). Dose escalation ranges include 1, 3, 10, 30, 100, 300 1000, and 300 x 10^5 Treg/kg.<br>* Other names: Treg cells;Drug: Sirolimus<br>* Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180.<br>* Other names: Rapamune®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Nine dose levels of CD4+CD25+ Treg are scheduled with the doses being 1, 3, 10, 30, 30+30, 100, 300, 1000, and 3000 x 10^5 Treg/kg recipient body weight. The dose escalation will proceed in cohorts of one patient until the first dose limiting toxicity (DLT) is observed. | 48 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with detectable Treg cells | determined by polymerase chain reaction (PCR) and flow cytometry | Days 0, +1, +3, +7, and +14 after Treg cell infusion | 
| Number of Patients with grade II-IV and grade III-IV acute graft versus host disease (GVHD) | Patients will be assessed weekly for GVHD between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. Incidence of grades II-IV and grades III-IV GVHD by day 100 will be monitored. | Day 100 | 
| Number of patients with sustained donor engraftment |  | Day 100 | 
| Number of patients with double chimerism |  | 6 Months and 1 Year | 
| Incidence of neutrophil recovery after umbilical cord blood (UCB) transplantation |  | Day 42 | 
| Number of Patients with Chronic Graft Versus Host Disease (GVHD) |  | 1 Year | 
| Number of Patients with disease-free survival |  | Day 100 and 1 Year | 
| Number of Patients with Fungal and Viral Infections | Count of reported infections. | 1 Year | 
| Incidence of platelet recovery after umbilical cord blood (UCB) |  | 6 Months After Transplant | 
| Number of Patients with Disease Relapse |  | 1 Year | 
| Percent of Patients with Immune Cell Recovery |  | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic myelogenous leukemia, recurrent mantle cell lymphoma, prolymphocytic leukemia, advanced chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell lymphoma, follicular lymphoma, diffuse large cell lymphoma, anaplastic large cell lymphoma, Hodgkin lymphoma, multiple myeloma