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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01163201
• Other study ID #: 2009LS018
• Secondary ID: MT2009-030910M73
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• First received: May 26, 2010
• Last updated: November 29, 2017
• Start date: January 2014
• Est. completion date: January 2015

Study information

• Verified date: November 2017
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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)

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myeloid Leukemia
• Anemia, Refractory, with Excess of Blasts
• Blast Crisis
• Burkitt Lymphoma
• Burkitt's Lymphoma
• Chronic Lymphocytic Leukemia
• Chronic Myelogenous Leukemia in Blast Crisis
• Chronic Myeloproliferative Disease
• Follicular Lymphoma
• Hematologic Malignancy
• High Grade Non-Hodgkin's Lymphoma
• Large Cell Non-Hodgkin's Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoblastic Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, B-Cell, Marginal Zone
• Lymphoma, Follicular
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoplasmacytic Lymphoma
• Mantle-Cell Lymphoma
• Marginal Zone B-cell Lymphoma
• Myeloproliferative Disorders
• Neoplasms
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Prolymphocytic Lymphoma
• Small Lymphocytic Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

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

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

Locations

Country	Name	City	State
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Optimal Cell Dose Mixture	Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD	Day 0
Secondary	Determine incidence of infusional toxicity	reaction that occurs with 48 hours of product infusion	48 hours
Secondary	Incidence of neutrophil recovery	Determine the incidence of neutrophil recovery (absolute neutrophil count = 500/uL) at day 42	Day 42
Secondary	Incidence of double and single chimerism	Determine incidence of double and single unit chimerism at various time points	Day +21, Day +180, 1 Year
Secondary	Incidence of Viral and Fungal Infections	Determine incidence of viral and fungal infections at 1 year	1 Year
Secondary	1 Year Survival	Estimate the probability of survival at 1 year	1 Year
Secondary	Incidence of Grade III-IV Acute Graft-Versus-Host Disease	Determine the incidence of grade III-IV acute GVHD at day 100	Day 100
Secondary	Incidence of Treatment Related Death	Determine the incidence of treatment related mortality (TRM) at 6 months	6 Months
Secondary	Incidence of Platelet Recovery	Determine the incidence of platelet recovery (platelet count = 50,000/uL) at 1 year	1 Year
Secondary	Incidence of Chronic Graft-Versus-Host Disease	Determine the incidence of chronic GVHD at 1 year	1 Year
Secondary	Incidence of Relapse	Determine the incidence of relapse at 1 year	1 Year