T-Regulatory Cell Infusion Post Umbilical Cord Blood Transplant in Patients With Advanced Hematologic Cancer
Condition: Leukemia; Lymphoma; Multiple Myeloma; Plasma Cell Neoplasm; Myelodysplastic Syndromes
MeSH terms: Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1

Summary: 
      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: 
      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.
    

Intervention name(s): umbilical cord blood transplantation; Allopurinol; fludarabine phosphate; Cyclophosphamide; Total body irradiation; Treg infusion; Sirolimus
Intervention type(s): Biological; Drug; Drug; Drug; Radiation; Biological; Drug
Intervention description(s): Infusion of umbilical cord blood; Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.; 40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2; 50 mg/kg intravenous over 2 hours on Day -6; 200 cGy on Day -1; 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.; 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.
Other intervention name(s): UCB transplant; Zyloprim; Fludara; Cytoxan; radiation; Treg cells; Rapamune®
Intervention MeSH terms: Sirolimus; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Allopurinol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: 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