Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation
- 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
- 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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Claudio G. Brunstein, MD, PhD
Masonic Cancer Center, University of Minnesota
United States: Food and Drug Administration
|Masonic Cancer Center at University of Minnesota||Minneapolis, Minnesota 55455|