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

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Completed

CT.gov ID

NCT00602693

Collaborator

(none)

Enrollment

Location

Arm

92.8

Actual Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma Multiple Myeloma Plasma Cell Neoplasm Myelodysplastic Syndromes	Biological: umbilical cord blood transplantation Drug: Allopurinol Drug: fludarabine phosphate Drug: Cyclophosphamide Radiation: Total body irradiation Biological: Treg infusion Drug: Sirolimus	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Actual Study Start Date :

Jul 23, 2007

Actual Primary Completion Date :

Sep 25, 2014

Actual Study Completion Date :

Apr 16, 2015

Arms and Interventions

Arm	Intervention/Treatment
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 Names: UCB transplant Drug: Allopurinol Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis. Other Names: Zyloprim Drug: fludarabine phosphate 40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2 Other Names: Fludara Drug: Cyclophosphamide 50 mg/kg intravenous over 2 hours on Day -6 Other Names: Cytoxan Radiation: Total body irradiation 200 cGy on Day -1 Other Names: radiation Biological: 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 Names: Treg cells Drug: 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 Names: Rapamune®

Arm

Intervention/Treatment

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 Names:

UCB transplant

Drug: Allopurinol

Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.

Other Names:

Zyloprim

Drug: fludarabine phosphate

40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2

Other Names:

Fludara

Drug: Cyclophosphamide

50 mg/kg intravenous over 2 hours on Day -6

Other Names:

Cytoxan

Radiation: Total body irradiation

200 cGy on Day -1

Other Names:

radiation

Biological: 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 Names:

Treg cells

Drug: 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 Names:

Rapamune®

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose [48 Hours]
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.

Secondary Outcome Measures

Number of patients with detectable Treg cells [Days 0, +1, +3, +7, and +14 after Treg cell infusion]
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) [Day 100]
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 [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 [1 Year]
Count of reported infections.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators

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