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

Primary Purpose

Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fludarabine Phosphate
Tacrolimus
Thiotepa
Total-Body Irradiation (TBI)
Magnetic Affinity Cell Sorting
Peripheral Blood Stem Cell Transplantation
Allogeneic Hematopoietic Stem Cell Transplantation
T Cell-Depleted Hematopoietic Stem Cell Transplantation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring 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

Eligibility Criteria

14 Years - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Yale University School of Medicine/Yale New Haven Hospital
  • Fred Hutchinson Cancer Research Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm 1

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD
Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.
Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant
Graft failure is defined as either a failure to reach an ANC of >500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC <100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.

Secondary Outcome Measures

Transplant-related Mortality by Day 100
Number of participants who died due to transplant-related issues within the first 100 days of transplant
Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant
Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.
Number of Participants With Chronic GVHD
Chronic GVHD measured by meeting NIH criteria and treated with immune suppression

Full Information

First Posted
June 4, 2009
Last Updated
August 10, 2020
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00914940
Brief Title
Selective Depletion of CD45RA+T Cells From Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Terminated
Why Stopped
Did not reach one of the primary endpoints of decreased total acute GVHD
Study Start Date
December 17, 2009 (Actual)
Primary Completion Date
December 1, 2019 (Actual)
Study Completion Date
May 26, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Advagraf, FK 506, Prograf, Protopic
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
Oncotiotepa, STEPA, TESPA, Tespamin, Tespamine, TSPA
Intervention Description
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).
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation (TBI)
Other Intervention Name(s)
TBI
Intervention Description
TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).
Intervention Type
Other
Intervention Name(s)
Magnetic Affinity Cell Sorting
Other Intervention Name(s)
Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi)
Intervention Description
Device
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, Peripheral Blood Progenitor Cell Transplantation, Transplantation, Peripheral Blood Stem Cell
Intervention Description
Patient will undergo a PBSC transplantation
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Intervention Description
Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation
Intervention Type
Biological
Intervention Name(s)
T Cell-Depleted Hematopoietic Stem Cell Transplantation
Intervention Description
Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation
Primary Outcome Measure Information:
Title
Number of Participants With Acute Graft-vs-host Disease (GVHD): Grade I-IV, Including Those With no Reportable Acute GVHD
Description
Number of participants with aGVHD and severity of aGVHD within the first 360 days post-transplant as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening.
Time Frame
Within 360 days of transplant
Title
Number of Participants Who Did Not Engraft After Receiving a CD45RA+ T Cell Depleted PBSC Transplant
Description
Graft failure is defined as either a failure to reach an ANC of >500/uL for 3 consecutive days by day 28 post-transplant, or an irreversible decrease in ANC <100 after an established donor graft, unless there is a reasonable explanation such as a viral infection or drug effect that may be responsible for a reversible decrease in ANC.
Time Frame
Up to 5 years post transplant
Secondary Outcome Measure Information:
Title
Transplant-related Mortality by Day 100
Description
Number of participants who died due to transplant-related issues within the first 100 days of transplant
Time Frame
Transplant to day 100
Title
Number of Participants Who Have Relapsed Within 5 Years of CD45RA+ T Cell Depleted PBSC Transplant
Description
Relapse is defined by the presence of malignant cells in marrow, peripheral blood, or extramedullary sites by histopathology. Testing for recurrent malignancy in the blood and bone marrow performed by monitoring the CBC and bone marrow at Day 28, 58, 80, 360, and as needed for suspected relapse.
Time Frame
Up to 5 years post transplant
Title
Number of Participants With Chronic GVHD
Description
Chronic GVHD measured by meeting NIH criteria and treated with immune suppression
Time Frame
Up to 5 years post transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marie Bleakley, MD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Warren Shlomchik, MD
Organizational Affiliation
Yale University School of Medicine/Yale New Haven Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University School of Medicine/Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109-1024
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35007144
Citation
Bleakley M, Sehgal A, Seropian S, Biernacki MA, Krakow EF, Dahlberg A, Persinger H, Hilzinger B, Martin PJ, Carpenter PA, Flowers ME, Voutsinas J, Gooley TA, Loeb K, Wood BL, Heimfeld S, Riddell SR, Shlomchik WD. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease. J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.
Results Reference
derived
PubMed Identifier
26053664
Citation
Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8.
Results Reference
derived

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

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