Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases
NCT ID: NCT00376519
Last Updated: 2017-12-02
Study Results
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Basic Information
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TERMINATED
PHASE1
3 participants
INTERVENTIONAL
2007-05-31
2008-03-31
Brief Summary
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PURPOSE: This phase I trial is studying the side effects and best dose of umbilical cord blood T-regulatory cell infusion followed by donor umbilical cord blood transplant in treating patients with high-risk leukemia or other hematologic diseases.
Detailed Description
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Primary
* Determine the maximum tolerated dose of umbilical cord blood (UCB)-derived CD4- and CD25-positive T-regulatory (Treg) cell infusion followed by double unrelated donor UCB transplantation in patients with high-risk leukemia or other hematologic diseases.
Secondary
* Determine the speed of neutrophil and platelet recovery at day 42 in these patients.
* Determine the incidence of "double chimerism" (e.g., engraftment of both UCB units) at day 21 in these patients.
* Determine the risk of severe grade III-IV acute graft-versus-host disease (GVHD) at day 100 in these patients.
* Determine the risk of chronic GVHD at 1 year post transplantation in these patients.
* Determine the probability of survival at 100 days and 1 year post transplantation in these patients.
OUTLINE: This is an open-label, dose-escalation study of CD4- and CD25-positive umbilical cord blood (UCB)-derived T-regulatory cells (Treg).
* Preparative therapy: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -9 to -7 and cyclophosphamide IV over 2 hours on days -8 and -7 (1 hour after fludarabine infusion). Patients then undergo total-body irradiation (TBI) twice daily on days -5 to -2.
* UCB-derived Treg infusion: Patients receive UCB-derived Treg cells IV on day -1.
* Double unrelated donor UCB transplantation: Patients undergo double unrelated donor UCB transplantation by IV infusion on day 0.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours or orally 2 or 3 times daily beginning on day -3 and continuing until day 100, followed by a taper to day 180, in the absence of GVHD. Patients also receive mycophenolate mofetil (MMF) orally or IV twice daily on days -3 to 30 or 7 days after engraftment, whichever is later, in the absence of acute GVHD\*. If no donor engraftment occurs, MMF may be continued at the discretion of the attending physician.
NOTE: \*If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days after GVHD is controlled (e.g., resolution of skin rash, vomiting, and diarrhea).
Cohorts of 3-6 patients receive escalating doses of UCB-derived Treg cells until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience nonhematologic dose-limiting toxicity within 48 hours of Treg cell infusion. At least 6 patients are treated at the MTD.
Conditions
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Keywords
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Transplant with Treg Cells
Patients receive preparative therapy with Fludarabine, cyclophosphamide, total body irradiation and Treg infusion followed by umbilical cord blood transplantation.
cyclophosphamide
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush and mesna (MT(S)9006) on day -8 and -7 one hour after fludarabine infusion.
cyclosporine
Will be administered beginning on day -3 and adjusted to maintain a level of \>200. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours.
fludarabine phosphate
Fludarabine 25 mg/m\^2/day will be administered as a 1 hour intravenous infusion on days -9 through -7.
mycophenolate mofetil
All patients will begin mycophenolate mofetil (MMF) on day -3, at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).
Treg cell infusion
On day -1 prior to UCB transplantation, Treg cells will be infused IV without in-line filtration. A semi-log dose escalation of CD4+CD25+ Treg cells is scheduled with 3 patients at each step. Doses will be 0.1 x 10\^6/kg, 0.3 x 10\^6/kg, 1 x 10\^6/kg and 3 x 10\^6/kg weight (determined on the day prior to administration of the preparative therapy).
umbilical cord blood transplantation
Following the administration of the preparative therapy, all subjects will undergo UCB transplantation. The UCB will be administrated by IV infusion without in-line filtration.
total-body irradiation
Radiotherapy: 165 cGy will be administered on day -5 through -2 two fractions each day.
Interventions
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cyclophosphamide
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush and mesna (MT(S)9006) on day -8 and -7 one hour after fludarabine infusion.
cyclosporine
Will be administered beginning on day -3 and adjusted to maintain a level of \>200. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours.
fludarabine phosphate
Fludarabine 25 mg/m\^2/day will be administered as a 1 hour intravenous infusion on days -9 through -7.
mycophenolate mofetil
All patients will begin mycophenolate mofetil (MMF) on day -3, at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).
Treg cell infusion
On day -1 prior to UCB transplantation, Treg cells will be infused IV without in-line filtration. A semi-log dose escalation of CD4+CD25+ Treg cells is scheduled with 3 patients at each step. Doses will be 0.1 x 10\^6/kg, 0.3 x 10\^6/kg, 1 x 10\^6/kg and 3 x 10\^6/kg weight (determined on the day prior to administration of the preparative therapy).
umbilical cord blood transplantation
Following the administration of the preparative therapy, all subjects will undergo UCB transplantation. The UCB will be administrated by IV infusion without in-line filtration.
total-body irradiation
Radiotherapy: 165 cGy will be administered on day -5 through -2 two fractions each day.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Patient must be 18-45 years of age.
* Patients must have three partially HLA matched UCB units. Units identified as the HSC source must be HLA matched at 4-6 HLA- A and B (at low to intermediate resolution) and DRB1 (at high resolution), and the units must be HLA matched at 4-6 HLA- A, B, DRB1 antigens with each other. Total cryopreserved HSC graft cell dose must be \>2.5 x 107 nucleated cells per kilogram recipient body weight. Also, the two umbilical cord blood (UCB) units must be ABO-matched.
* The UCB unit identified as the Treg source must be HLA matched at 4-6 HLA antigens with the patient (without an HLA or ABO matching criterion with the UCB HSC source).
Disease Criteria
* Patients must have a hematological malignancy as listed below:
* Acute myelogenous leukemia: high risk CR1 (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, or \>2 cycles to obtain complete remission (CR); second or greater CR. Must be in remission by morphology (\<5% blasts within normocellular marrow).
* Acute lymphocytic leukemia: high risk CR1 as evidenced by high risk cytogenetics \[t(9;22), t (1:19), t(4;11) or other MLL rearrangements\] or \> 1 cycle to obtain CR; second or greater CR.
* Chronic myelogenous leukemia resistant to imatinib therapy
* Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be \< 10% by a representative bone marrow aspirate morphology (otherwise induction chemotherapy to achieve \< 10% blasts is required pre-transplant).
* Advanced myelofibrosis
* Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma that have progressed after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant.
* Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+.
* Large cell non-Hodgkins lymphoma (NHL) \> CR2/\> PR2. Patients in CR2/PR2 with initial short remission(\<6 months) are eligible.
* Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II \<1 year.
* Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin \> 3 mg/L, may be considered for this protocol after initial therapy.
* Recipients will have a Karnofsky score \> 80% and have acceptable organ function ie creatinine \< 2.0, bilirubin, AST/ALT, ALP \< 2 x normal, pulmonary function \> 50% normal, left ventricular ejection fraction \> 45%. Note: All patients with a creatinine \> 1.2 or a history of renal dysfunction must have creatinine clearance (must be \> 40 ml/min to be eligible).
* Recipients will sign informed consent approved by the Committee on the Use of Human Subjects at the University of Minnesota.
Exclusion Criteria
* Evidence of HIV infection or known HIV positive serology
* Current active infection
* Available HLA matched sibling donor.
* CML in active blast crisis
18 Years
45 Years
ALL
No
Sponsors
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Masonic Cancer Center, University of Minnesota
OTHER
Responsible Party
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Principal Investigators
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Claudio G. Brunstein, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Masonic Cancer Center, University of Minnesota
Locations
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Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States
Countries
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Other Identifiers
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UMN-0502M67473
Identifier Type: OTHER
Identifier Source: secondary_id
UMN-MT2005-01
Identifier Type: OTHER
Identifier Source: secondary_id
UMN-2005LS011
Identifier Type: -
Identifier Source: org_study_id