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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00602693
First received: January 10, 2008
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

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 Intervention 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

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 39
Study Start Date: July 2007
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 transplant
Drug: Allopurinol
Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.
Other Name: Zyloprim
Drug: fludarabine phosphate
40 mg/m^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2
Other Name: Fludara
Drug: Cyclophosphamide
50 mg/kg intravenous over 2 hours on Day -6
Other Name: Cytoxan
Radiation: Total body irradiation
200 cGy on Day -1
Other Name: 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 Name: 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 Name: Rapamune®

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00602693

Contacts
Contact: Claudio Brunstein, MD 612-625-3918 bruns072@umn.edu
Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org

Locations
United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Clinical Trials Office - Masonic Cancer Center at University o    612-624-2620      
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
  More Information

Additional Information:
No publications provided by Masonic Cancer Center, University of Minnesota

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00602693     History of Changes
Other Study ID Numbers: 2007LS022, MT2006-01, 0701M00303
Study First Received: January 10, 2008
Last Updated: May 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
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

Additional relevant MeSH terms:
Plasmacytoma
Neoplasms
Leukemia
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Allopurinol
Fludarabine monophosphate
Vidarabine
Cyclophosphamide
Sirolimus
Everolimus
Fludarabine
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014