Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

This study is currently recruiting participants.
Verified August 2012 by Yale University
Sponsor:
Collaborators:
Fred Hutchinson Cancer Research Center
Information provided by (Responsible Party):
Yale University
ClinicalTrials.gov Identifier:
NCT00914940
First received: June 4, 2009
Last updated: August 10, 2012
Last verified: August 2012

June 4, 2009
August 10, 2012
October 2009
August 2020   (final data collection date for primary outcome measure)
  • Rate of grade II-IV acute graft-vs-host disease (GVHD) [ Time Frame: Start of study to day 100 ] [ Designated as safety issue: Yes ]
  • Rate of engraftment [ Time Frame: Up to 5 years post transplant ] [ Designated as safety issue: Yes ]
  • Grade II-IV acute graft-vs-host disease (GVHD) [ Designated as safety issue: No ]
  • Graft failure [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00914940 on ClinicalTrials.gov Archive Site
  • Evaluation of recovery of T-cell immunity to pathogens [ Time Frame: Start of study to day 100 ] [ Designated as safety issue: Yes ]
  • Rate of transplant-related mortality at day 100 [ Time Frame: Start of study to day 100 ] [ Designated as safety issue: Yes ]
  • Rate of relapse [ Time Frame: Up to 5 years post transplant ] [ Designated as safety issue: Yes ]
  • Rate and severity of chronic GVHD [ Time Frame: Up to 1 year post transplant ] [ Designated as safety issue: Yes ]
  • Transplant-related mortality at day 100 [ Designated as safety issue: No ]
  • Relapse [ Designated as safety issue: No ]
  • Grade III-IV acute GVHD [ Designated as safety issue: No ]
  • Chronic GVHD [ Designated as safety issue: No ]
  • Rate of engraftment [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD

RATIONALE: Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment that can cure acute leukemia and myelodysplasia. After giving the patient chemotherapy and total body irradiation to stop the growth of cancer and remove the patient's diseased bone marrow, healthy stem cells from a donor are infused into the patient to replace the patient's bone marrow and make red and white blood cells and platelets. Unfortunately HSCT is often complicated by 'graft versus host disease' (GVHD) in which the transplanted cells from a donor can make an immune response against the body's normal cells and cause tissue damage and severe symptoms. Removing a subset of the donor T cells, called 'naive T cells', before transplant may reduce the frequency and intensity of GVHD.

PURPOSE: This phase II trial will determine whether the removal of the naive T cells from donor cells can decrease the rate and severity of graft-vs-host disease while preserving specific immunity against infections in patients with acute leukemia or advanced myelodysplastic syndromes.

OBJECTIVES:

Primary

  • Estimate the probability of grades II-IV acute graft-vs-host disease (GVHD) in patients with acute leukemia or advanced myelodysplastic syndromes treated with CD45RA+ T-cell-depleted allogeneic peripheral blood stem cell transplantation and compare this to relevant historical experience.
  • Estimate the probability of graft failure in these patients.

Secondary

  • Evaluate immune reconstitution and pathogen-specific T-cell reconstitution in these patients.
  • Estimate the probability of transplant-related mortality by day 100 in these patients.
  • Estimate the probability of relapse in these patients.
  • Estimate the probability and severity of chronic GVHD in these patients.

OUTLINE: This is a multicenter study.

  • Myeloablative conditioning regimen: Patients undergo total body irradiation twice daily for 4 days (Days -10 to -7) Patients also receive thiotepa IV over 4 hours for 2 days (Days -6 and -5) and fludarabine phosphate IV over 30 minutes for 5 days (Days -6 to -2.)
  • Transplantation: Patients receive a CD34+ enriched allogeneic peripheral blood stem cell (PBSC) product followed by a CD45RA+ T-cell-depleted allogeneic PBSC product on day 0.
  • Graft-vs-host disease (GVHD) prophylaxis: Patients will receive Tacrolimus as per cohort 1. If the rate of grade II-IV acute GVHD in the first 35 patients is significantly reduced (compared to historical controls), subsequent patients are enrolled in cohort 2.

    • Cohort 1: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50, followed by a standard taper in the absence of grade II-IV acute GVHD.
    • Cohort 2: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30, followed by a rapid taper in the absence of grade II-IV acute GVHD.

Patients are followed actively for at least 1 year post transplant.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Graft Versus Host Disease
  • Leukemia
  • Myelodysplastic Syndromes
  • Drug: Fludarabine Phosphate
    Fludarabine will be administered in a dose of 25 mg/m2/day IV over approximately 30 minutes for 5 consecutive days (day -6 to -2). The total dose of fludarabine will be 125 mg/m2.
    Other Names:
    • 2-F-ara-AMP
    • Beneflur
    • Fludara
  • Drug: Tacrolimus

    Tacrolimus will be administered beginning on day -1 at a dose of 0.03 mg/kg/day by continuous IV infusion.

    For the first cohort of 35 patients, if there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus should then be tapered at the rate of approximately 5% of the day 50 dose each week for liquid, and 20% of the day 50 dose per month for capsules.

    In the second cohort of 25 patients if there is no evidence of grade II GVHD on or prior to day 30, tacrolimus should then be tapered at the rate of approximately 8% of the day 30 dose each week for liquid, and 33% of the day 30 dose per month for capsules.

    Other Names:
    • Advagraf
    • FK 506
    • Prograf
    • Protopic
  • Drug: Thiotepa
    Thiotepa will be administered in a dose of 5 mg/kg/day (adjusted body weight) IV over approximately 4 hours for 2 consecutive days (day -6 and day -5).
    Other Names:
    • Oncotiotepa
    • STEPA
    • TESPA
    • Tespamin
    • Tespamine
    • TSPA
  • Radiation: Total-Body Irradiation (TBI)
    TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
    Other Name: TBI
  • Other: Magnetic Affinity Cell Sorting
    Device
    Other Name: Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Patient will undergo a PBSC transplantation
    Other Names:
    • PBPC transplantation
    • PBSC transplantation
    • Peripheral Blood Progenitor Cell Transplantation
    • Transplantation
    • Peripheral Blood Stem Cell
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation
  • Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
    Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation
Experimental: Arm 1

CONDITIONING: Patients undergo total-body irradiation twice daily on days -10 to -7. Patients also receive thiotepa IV over 4 hours on days -6 and -5 and fludarabine IV over 30 minutes on days -6 to -2. TRANSPLANTATION: Patients undergo infusion of CD34+ enriched allogeneic peripheral blood stem cells (PBSC) followed by CD45RA+ T-cell-depleted allogeneic PBSC on day 0.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Cohort A: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 50 followed by standard taper in the absence of grade II-IV acute GVHD. Cohort B: Patients receive tacrolimus IV continuously or orally twice daily beginning on day -1 and continuing until day 30 followed by rapid taper in the absence of grade II-IV acute GVHD.

Interventions:
  • Drug: Fludarabine Phosphate
  • Drug: Tacrolimus
  • Drug: Thiotepa
  • Radiation: Total-Body Irradiation (TBI)
  • Other: Magnetic Affinity Cell Sorting
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
  • Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
60
August 2020
August 2020   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following:

    • Acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) in first or subsequent remission
    • ALL or AML in relapse or primary refractory ALL or AML with a circulating blast count ≤ 10,000/mm^3
    • Refractory anemia with excess blasts (RAEB) (RAEB-1 or RAEB-2) if the patient has received induction chemotherapy within the past 60 days
  • Appropriate candidate for allogeneic hematopoietic stem cell transplantation (HSCT)
  • No CNS involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy

PATIENT CHARACTERISTICS:

  • Age 14-55
  • Creatinine < 1.5 mg/dL
  • Cardiac ejection fraction > 45%
  • DLCO corrected > 60% of predicted
  • Total bilirubin < 2 times upper limit of normal (ULN) (unless attributed to Gilbert syndrome)
  • AST and ALT < 2 times ULN
  • Not pregnant or nursing
  • Fertile patients must use effective contraception during and for 12 months after transplantation
  • HIV negative
  • No co-existing disease (other than leukemia or RAEB) that would limit life expectancy to < 3 months
  • No uncontrolled infection that, in the opinion of the consulting infectious disease physician, would contraindicate myeloablative HSCT
  • No other medical condition that would contraindicate HSCT
  • No known hypersensitivity to tacrolimus

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior HSCT
  • No concurrent participation in other experimental studies for the prevention of graft-vs-host disease

DONOR CHARACTERISTICS:

  • Genotypic or phenotypic HLA-identical related donor
  • Able to donate peripheral blood stem cells
  • Age > 14 years
  • Applicable to male patients only: No female donors who have previously given birth to a male child or have had a pregnancy beyond the first trimester miscarriage or termination of pregnancy or nursing
  • No donors who have received blood transfusions
  • No CD45 Mutation with aberrant CD45RA isoform expression
Both
14 Years to 55 Years
No
Not Provided
United States
 
NCT00914940
FHCRC-2222.00, P30CA015704, P01CA018029, IR-6907, CDR0000644201, 0903004832
Yes
Yale University
Yale University
  • National Cancer Institute (NCI)
  • Fred Hutchinson Cancer Research Center
Principal Investigator: Marie Bleakley, MD Fred Hutchinson Cancer Research Center
Principal Investigator: Warren Shlomchik, MD Yale University School of Medicine/Yale New Haven Hospital
Yale University
August 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP