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

NCT ID: NCT00914940

Last Updated: 2020-08-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-12-17
• Study Completion Date: 2020-05-26

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.

Conditions

Graft Versus Host Disease; Leukemia; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Fludarabine Phosphate

Intervention Type: DRUG

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.

Tacrolimus

Intervention Type: DRUG

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.

Thiotepa

Intervention Type: DRUG

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).

Total-Body Irradiation (TBI)

Intervention Type: RADIATION

TBI will be given as 165 cGy fractions twice per day x 4 days - total dose 1320cGy (days -10 to -7).

Magnetic Affinity Cell Sorting

Intervention Type: OTHER

Device

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Patient will undergo a PBSC transplantation

Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

T Cell-Depleted Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Interventions

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.

Intervention Type: 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.

Intervention Type: 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).

Intervention Type: DRUG

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).

Intervention Type: RADIATION

Magnetic Affinity Cell Sorting

Device

Intervention Type: OTHER

Peripheral Blood Stem Cell Transplantation

Patient will undergo a PBSC transplantation

Intervention Type: PROCEDURE

Allogeneic Hematopoietic Stem Cell Transplantation

Patients who are considered appropriate candidates for allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

T Cell-Depleted Hematopoietic Stem Cell Transplantation

Patients who are eligible will receive a T Cell-Depleted Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

Other Intervention Names

2-F-ara-AMP; Beneflur; Fludara; Advagraf; FK 506; Prograf; Protopic; Oncotiotepa; STEPA; TESPA; Tespamin; Tespamine; TSPA; TBI; Magnetic-Activated Cell Sorter (CliniMACS, Miltenyi); PBPC transplantation; PBSC transplantation; Peripheral Blood Progenitor Cell Transplantation; Transplantation; Peripheral Blood Stem Cell

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 14 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marie Bleakley, MD

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Warren Shlomchik, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University School of Medicine/Yale New Haven Hospital

Locations

Yale University School of Medicine/Yale New Haven Hospital

New Haven, Connecticut, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35007144 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26053664 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P01CA018029

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IR-6907

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000644201

Identifier Type: REGISTRY

Identifier Source: secondary_id

0903004832

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-2010-00713

Identifier Type: REGISTRY

Identifier Source: secondary_id

RG2810004

Identifier Type: OTHER

Identifier Source: secondary_id

2222.00

Identifier Type: -

Identifier Source: org_study_id