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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 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: June 12, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Graft Versus Host Disease
Leukemia
Myelodysplastic Syndromes
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
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Yale University:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 60
Study Start Date: October 2009
Estimated Study Completion Date: August 2020
Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   14 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00914940

Locations
United States, Connecticut
Yale University School of Medicine/Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06520
Contact: Yale Cancer Center    203-785-5702      
Contact: Warren Shlomchik, MD    203-737-2478      
Principal Investigator: Warren Shlomchik, MD         
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109-1024
Contact: Seattle Cancer Care Alliance    800-804-8824      
Contact: Colette Chaney, RN    206-667-5823      
Principal Investigator: Marie Bleakley, MD         
Sponsors and Collaborators
Yale University
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Marie Bleakley, MD Fred Hutchinson Cancer Research Center
Principal Investigator: Warren Shlomchik, MD Yale University School of Medicine/Yale New Haven Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT00914940     History of Changes
Other Study ID Numbers: FHCRC-2222.00, P30CA015704, P01CA018029, IR-6907, CDR0000644201, 0903004832
Study First Received: June 4, 2009
Last Updated: June 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Yale University:
graft versus host disease
adult acute lymphoblastic leukemia in remission
recurrent adult acute lymphoblastic leukemia
childhood acute lymphoblastic leukemia in remission
recurrent childhood acute lymphoblastic leukemia
adult acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
childhood acute myeloid leukemia in remission
recurrent childhood acute myeloid leukemia
childhood myelodysplastic syndromes
previously treated myelodysplastic syndromes
refractory anemia with excess blasts
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes

Additional relevant MeSH terms:
Graft vs Host Disease
Leukemia
Myelodysplastic Syndromes
Preleukemia
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Thiotepa
Fludarabine
Fludarabine phosphate
Tacrolimus
Vidarabine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 01, 2014