T-Regulatory Cell Infusion Post Umbilical Cord Blood Transplant in Patients With Advanced Hematologic Cancer
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.
Plasma Cell Neoplasm
Biological: umbilical cord blood transplantation
Drug: fludarabine phosphate
Radiation: Total body irradiation
Biological: Treg infusion
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation|
- Maximum tolerated dose [ Time Frame: 48 Hours ] [ Designated as safety issue: Yes ]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.
- Number of patients with detectable Treg cells [ Time Frame: Days 0, +1, +3, +7, and +14 after Treg cell infusion ] [ Designated as safety issue: No ]determined by polymerase chain reaction (PCR) and flow cytometry
- Number of Patients with grade II-IV and grade III-IV acute graft versus host disease (GVHD) [ Time Frame: Day 100 ] [ Designated as safety issue: No ]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.
- Number of patients with sustained donor engraftment [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
- Number of patients with double chimerism [ Time Frame: 6 Months and 1 Year ] [ Designated as safety issue: No ]
- Incidence of neutrophil recovery after umbilical cord blood (UCB) transplantation [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
- Number of Patients with Chronic Graft Versus Host Disease (GVHD) [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
- Number of Patients with disease-free survival [ Time Frame: Day 100 and 1 Year ] [ Designated as safety issue: No ]
- Number of Patients with Fungal and Viral Infections [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]Count of reported infections.
- Incidence of platelet recovery after umbilical cord blood (UCB) [ Time Frame: 6 Months After Transplant ] [ Designated as safety issue: Yes ]
- Number of Patients with Disease Relapse [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
- Percent of Patients with Immune Cell Recovery [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2007|
|Estimated Study Completion Date:||July 2016|
|Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
Experimental: UCB post-transplant Treg Cell Infusion
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
Infusion of umbilical cord blood
Other Name: UCB transplantDrug: Allopurinol
Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.
Other Name: ZyloprimDrug: fludarabine phosphate
40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2
Other Name: FludaraDrug: Cyclophosphamide
50 mg/kg intravenous over 2 hours on Day -6
Other Name: CytoxanRadiation: Total body irradiation
200 cGy on Day -1
Other Name: radiationBiological: Treg infusion
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.
Other Name: Treg cellsDrug: Sirolimus
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 Name: Rapamune®
- Determine the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00602693
|United States, Minnesota|
|Masonic Cancer Center at University of Minnesota|
|Minneapolis, Minnesota, United States, 55455|
|Principal Investigator:||Claudio G. Brunstein, MD, PhD||Masonic Cancer Center, University of Minnesota|
|Principal Investigator:||Margaret L. MacMillan, MD||Masonic Cancer Center, University of Minnesota|