T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01163201

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD).

In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancy Acute Myeloid Leukemia Acute Lymphocytic Leukemia Chronic Myelogenous Leukemia in Blast Crisis Anemia, Refractory, With Excess of Blasts Chronic Myeloproliferative Disease Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Marginal Zone B-cell Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle-Cell Lymphoma Prolymphocytic Lymphoma Large Cell Non-Hodgkin's Lymphoma Lymphoblastic Lymphoma Burkitt's Lymphoma High Grade Non-Hodgkin's Lymphoma	Biological: Treg cells Biological: CD3+ Teff cells Drug: Fludarabine Drug: Cyclophosphamide Radiation: Total body irradiation Biological: Umbilical cord blood transplantation	Phase 1/Phase 2

Detailed Description

Based on prior studies, the first patient will start at lowest dose combination (3 x 10^{6/kg
of Treg and 3 x 10}6/kg of CD3+ Teff cells).

One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a "successful step", then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a "failed step", then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations.

An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Optimization of the T Regulatory Cell and T Effector Cell Doses in Recipients of Double UCB Transplantation for Treatment of Hematological Malignancies

Study Start Date :

Jan 1, 2014

Anticipated Primary Completion Date :

Jan 1, 2015

Anticipated Study Completion Date :

Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treg Plus CD3+Teff Treatment Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation	Biological: Treg cells Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10^6/kg, 10 x 10^6/kg, 30 x 10^6/kg, 100 x 10^6/kg and 300 x 10^6/kg) Biological: CD3+ Teff cells Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10^6 cells/kg, 6 x 10^6 cells/kg, 9 x 10^6 cells/kg, 12 x 10^6 cells/kg, and 15 x 10^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts Drug: Fludarabine Given intravenously on Days -8 through -6, 25 mg/m^2 over 1 hour Other Names: Fludara Drug: Cyclophosphamide Given intravenously on Day -7 and -6, 60 mg/kg Other Names: Cytoxan Radiation: Total body irradiation Given on Days -4 through -2, 165 cGY twice a day. Biological: Umbilical cord blood transplantation Infusion given on day 0 Other Names: UCBT

Arm

Intervention/Treatment

Experimental: Treg Plus CD3+Teff Treatment

Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation

Biological: Treg cells

Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10^6/kg, 10 x 10^6/kg, 30 x 10^6/kg, 100 x 10^6/kg and 300 x 10^6/kg)

Biological: CD3+ Teff cells

Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10^6 cells/kg, 6 x 10^6 cells/kg, 9 x 10^6 cells/kg, 12 x 10^6 cells/kg, and 15 x 10^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts

Drug: Fludarabine

Given intravenously on Days -8 through -6, 25 mg/m^2 over 1 hour

Other Names:

Fludara

Drug: Cyclophosphamide

Given intravenously on Day -7 and -6, 60 mg/kg

Other Names:

Cytoxan

Radiation: Total body irradiation

Given on Days -4 through -2, 165 cGY twice a day.

Biological: Umbilical cord blood transplantation

Infusion given on day 0

Other Names:

UCBT

Outcome Measures

Primary Outcome Measures

Optimal Cell Dose Mixture [Day 0]
Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD

Secondary Outcome Measures

Determine incidence of infusional toxicity [48 hours]
reaction that occurs with 48 hours of product infusion
Incidence of neutrophil recovery [Day 42]
Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42
Incidence of double and single chimerism [Day +21, Day +180, 1 Year]
Determine incidence of double and single unit chimerism at various time points
Incidence of Viral and Fungal Infections [1 Year]
Determine incidence of viral and fungal infections at 1 year
1 Year Survival [1 Year]
Estimate the probability of survival at 1 year
Incidence of Grade III-IV Acute Graft-Versus-Host Disease [Day 100]
Determine the incidence of grade III-IV acute GVHD at day 100
Incidence of Treatment Related Death [6 Months]
Determine the incidence of treatment related mortality (TRM) at 6 months
Incidence of Platelet Recovery [1 Year]
Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year
Incidence of Chronic Graft-Versus-Host Disease [1 Year]
Determine the incidence of chronic GVHD at 1 year
Incidence of Relapse [1 Year]
Determine the incidence of relapse at 1 year

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Only patients requiring a double umbilical cord blood (UCB) transplant are to be considered for this study.

UCB Requirements

Three UCB units are required - one for Treg production and two for UCB transplant. The unrelated UCB donors must be 4-6/6 HLA-A, B, DRB1 matched with the recipient (HLA matching using molecular techniques: A and B to antigen level resolution and DR to allele level resolution). Suitable UCB units will be selected according to the University Of Minnesota UCB Graft Selection Algorithm.
Suitable UCB units must be ABO matched.

Disease Criteria:

Patients aged 18 to 55 years
Acute Myeloid Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy (if patient refuses or is disqualified from alternative protocols), or in 3rd or higher complete remission (CR).
Acute Lymphocytic Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy, or in 3rd or higher CR
Chronic Myelogenous Leukemia in Blast Crisis: with ≤10% residual blasts in the bone marrow aspirate after at least 1 cycle of induction chemotherapy in combination with a tyrosine kinase inhibitor (TKI)
Refractory Anemia with Excess Blasts: (≤ 10%) in representative bone marrow aspirate sample of blasts after 1 cycle of induction chemotherapy. If treated with hypomethylating agents, patients are eligible if blast count is ≤ 10% after 4 cycles or evidence of stable or progressive disease after at least 2 cycles.
Chronic Myeloproliferative Disease
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone B-Cell Lymphoma or Follicular Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
Large Cell Non-Hodgkin's Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other High-Grade NHL: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
Performance Status, Age, and Organ Function
Adequate performance status defined as a Karnofsky score ≥ 80%
Adequate organ function defined as:
Renal: creatinine < 2.0 mg/dL,
Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,
Pulmonary function: DLCOcorr > 50% normal,
Cardiac: left ventricular ejection fraction > 45%
Voluntary written informed consent signed before performance of any study-related procedure not part of normal medical care

Exclusion Criteria:

Available medically suitable HLA-identical related donor
Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
History of HIV infection
Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
Prior myeloablative transplant within the last 6 months
Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar) as part of their salvage therapy (not eligible for myeloablative umbilical cord blood transplant)