Brief Title
T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies
Official Title
Optimization of the T Regulatory Cell and T Effector Cell Doses in Recipients of Double UCB Transplantation for Treatment of Hematological Malignancies
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.
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 Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Optimal Cell Dose Mixture
Secondary Outcome
Determine incidence of infusional toxicity
Condition
Hematologic Malignancy
Intervention
Treg cells
Study Arms / Comparison Groups
Treg Plus CD3+Teff Treatment
Description: Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
0
Start Date
January 2014
Completion Date
January 2015
Primary Completion Date
January 2015
Eligibility Criteria
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)
Gender
All
Ages
18 Years - 55 Years
Accepts Healthy Volunteers
No
Contacts
Claudio Brunstein, MD, PhD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01163201
Organization ID
2009LS018
Secondary IDs
MT2009-03
Responsible Party
Sponsor
Study Sponsor
Masonic Cancer Center, University of Minnesota
Study Sponsor
Claudio Brunstein, MD, PhD, Principal Investigator, Masonic Cancer Center, University of Minnesota
Verification Date
November 2017