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Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation


Phase 1
18 Years
75 Years
Open (Enrolling)
Both
Leukemia, Lymphoma, Multiple Myeloma, Plasma Cell Neoplasm, Myelodysplastic Syndromes

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Trial Information

Phase I Study of Infusion of Umbilical Cord Blood (UCB) Derived CD25+CD4+ T-Regulatory (Treg) Cells After Nonmyeloablative Cord Blood Transplantation


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.


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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Description:

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.

Outcome Time Frame:

48 Hours

Safety Issue:

Yes

Principal Investigator

Claudio G. Brunstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota

Authority:

United States: Food and Drug Administration

Study ID:

2007LS022

NCT ID:

NCT00602693

Start Date:

July 2007

Completion Date:

July 2016

Related Keywords:

  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • relapsing chronic myelogenous leukemia
  • chronic phase chronic myelogenous leukemia
  • accelerated phase chronic myelogenous leukemia
  • recurrent mantle cell lymphoma
  • prolymphocytic leukemia
  • stage III chronic lymphocytic leukemia
  • stage IV chronic lymphocytic leukemia
  • recurrent small lymphocytic lymphoma
  • stage III small lymphocytic lymphoma
  • stage IV small lymphocytic lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • stage III grade 1 follicular lymphoma
  • stage IV grade 1 follicular lymphoma
  • stage III grade 2 follicular lymphoma
  • stage IV grade 2 follicular lymphoma
  • stage III grade 3 follicular lymphoma
  • stage IV grade 3 follicular lymphoma
  • contiguous stage II adult diffuse large cell lymphoma
  • noncontiguous stage II adult diffuse large cell lymphoma
  • recurrent adult diffuse large cell lymphoma
  • stage I adult diffuse large cell lymphoma
  • stage III adult diffuse large cell lymphoma
  • stage IV adult diffuse large cell lymphoma
  • recurrent childhood anaplastic large cell lymphoma
  • stage I childhood anaplastic large cell lymphoma
  • stage II childhood anaplastic large cell lymphoma
  • stage III childhood anaplastic large cell lymphoma
  • stage IV childhood anaplastic large cell lymphoma
  • childhood diffuse large cell lymphoma
  • childhood immunoblastic large cell lymphoma
  • recurrent childhood large cell lymphoma
  • recurrent adult Hodgkin lymphoma
  • stage I adult Hodgkin lymphoma
  • stage II adult Hodgkin lymphoma
  • stage III adult Hodgkin lymphoma
  • stage IV adult Hodgkin lymphoma
  • recurrent/refractory childhood Hodgkin lymphoma
  • stage I childhood Hodgkin lymphoma
  • stage II childhood Hodgkin lymphoma
  • stage III childhood Hodgkin lymphoma
  • stage IV childhood Hodgkin lymphoma
  • stage I multiple myeloma
  • stage II multiple myeloma
  • stage III multiple myeloma
  • extramedullary plasmacytoma
  • isolated plasmacytoma of bone
  • monoclonal gammopathy of undetermined significance
  • primary systemic amyloidosis
  • refractory multiple myeloma
  • refractory anemia with ringed sideroblasts
  • refractory anemia
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myeloid leukemia in remission
  • recurrent adult acute myeloid leukemia
  • untreated adult acute myeloid leukemia
  • childhood myelodysplastic syndromes
  • childhood acute myeloid leukemia in remission
  • recurrent childhood acute myeloid leukemia
  • untreated childhood acute myeloid leukemia and other myeloid malignancies
  • secondary acute myeloid leukemia
  • adult acute lymphoblastic leukemia in remission
  • recurrent adult acute lymphoblastic leukemia
  • childhood acute lymphoblastic leukemia in remission
  • recurrent childhood acute lymphoblastic leukemia
  • contiguous stage II adult lymphoblastic lymphoma
  • noncontiguous stage II adult lymphoblastic lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent childhood lymphoblastic lymphoma
  • stage I adult lymphoblastic lymphoma
  • stage I childhood lymphoblastic lymphoma
  • stage III adult lymphoblastic lymphoma
  • stage III childhood lymphoblastic lymphoma
  • stage IV adult lymphoblastic lymphoma
  • stage IV childhood lymphoblastic lymphoma
  • atypical chronic myeloid leukemia
  • Burkitt lymphoma
  • recurrent adult Burkitt lymphoma
  • stage III adult Burkitt lymphoma
  • stage IV adult Burkitt lymphoma
  • adult grade III lymphomatoid granulomatosis
  • childhood grade III lymphomatoid granulomatosis
  • recurrent adult grade III lymphomatoid granulomatosis
  • recurrent childhood grade III lymphomatoid granulomatosis
  • chronic myelomonocytic leukemia
  • juvenile myelomonocytic leukemia
  • recurrent marginal zone lymphoma
  • splenic marginal zone lymphoma
  • stage III marginal zone lymphoma
  • stage IV marginal zone lymphoma
  • contiguous stage II adult immunoblastic large cell lymphoma
  • noncontiguous stage II adult immunoblastic large cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • stage I adult immunoblastic large cell lymphoma
  • stage III adult immunoblastic large cell lymphoma
  • stage IV adult immunoblastic large cell lymphoma
  • recurrent childhood small noncleaved cell lymphoma
  • stage III childhood small noncleaved cell lymphoma
  • refractory cytopenia with multilineage dysplasia
  • refractory anemia with excess blasts in transformation
  • refractory anemia with excess blasts
  • myelodysplastic/myeloproliferative disease, unclassifiable
  • Neoplasms
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Lymphoma, Large-Cell, Immunoblastic
  • Lymphoma, Large-Cell, Anaplastic

Name

Location

Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455